Clinical Virology, Third Edition

• Chapter 2 : Respiratory Infections

  Author: John J. Treanor
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    This chapter describes the clinical syndromes of respiratory virus infection, the spectrum of viruses associated with these syndromes, and the pathophysiology of these illnesses. Many of the viruses associated with acute respiratory disease display a significant seasonal variation in incidence, especially in temperate climates. The majority of common colds are associated with infection with rhinoviruses or other picornaviruses, particularly when very sensitive techniques, such as polymerase chain reaction (PCR), are used for diagnosis. Viral pathogens associated with acute pharyngitis are summarized in this chapter. Pharyngitis is a typical component of acute influenza in which individuals experience the sudden onset of systemic symptoms of fever, myalgias, and malaise accompanied by upper respiratory signs and symptoms, including pharyngitis. The majority of cases of inspiratory stridor in children are caused by viral croup. In addition to causing croup and bronchiolitis, viral infection of the trachea and bronchi may cause tracheitis or tracheobronchitis. Antiviral therapy is available for some of the viruses responsible for bronchiolitis, but the use of such therapy for the most common etiology, respiratory syncytial virus (RSV), remains controversial. Viral pneumonia is an important cause of morbidity and mortality in individuals with compromised immune systems, with a broader spectrum of viral agents than seen in immunologically intact individuals. The general features of primary viral pneumonia are discussed using influenza as a model. Pathogenesis of other forms of viral pneumonia is also discussed.

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• Chapter 3 : Viral Central Nervous System Infections

  Authors: Kevin A. Cassady, Richard J. Whitley
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    Viral disease in the central nervous system (CNS) can be classified by pathogenesis. Neurologic disease is frequently categorized as either primary or postinfectious. Primary encephalitis results from direct viral entry into the CNS that produces clinically evident cortical or brain stem dysfunction. Meningitis and encephalitis represent separate clinical entities; however, a continuum exists between these distinct forms of disease. A change in a patient’s clinical condition can reflect disease progression with involvement of different regions of the brain. Epidemiological data in many cases provide clues to the etiology of the illness. Viral meningitis is a relatively benign self-limited illness, and pathological specimens are rarely available for study. The diagnosis of viral meningitis relied on viral culture, and CSF viral culture rates differ based on etiology. The fundamental principle of therapy for viral meningitis lies in the identification of potentially treatable diseases. Similar to the case with viral meningitis, passive reporting systems underestimate the incidence of viral encephalitis. The pathogenesis of encephalitis requires that viruses reach the CNS by hematogenous or neuronal spread. Patients with encephalitis, depending on the etiology and extent of CNS involvement, require treatment tailored to their clinical situation. The approach to a patient with a presumed CNS viral infection must be tailored to the severity and distribution of neurologic involvement. Improvements in ability to diagnose CNS infections will produce a better understanding of the pathogenesis and true extent of CNS viral disease.

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• Chapter 4 : Gastrointestinal Syndromes

  Authors: Manish Patel, Roger I. Glass
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    Gastroenteritis is one of the most common illnesses affecting infants, children, and adults and accounts for more than 2.5 million deaths annually in children under 5 years of age worldwide. This chapter concentrates on gastroenteritis and diarrhea caused specifically by viruses. The viral agents that are proven causes of gastroenteritis fall into four distinct families--rotaviruses (Reoviridae), human caliciviruses (Caliciviridae), enteric adenoviruses (Adenoviridae), and astroviruses (Astroviridae). All of these viruses cause clinical syndromes of diarrhea and vomiting that are generally similar, extraintestinal manifestations of disease are rare, and other disease syndromes associated with these viruses in humans have not been well documented. Some groups of people are at particularly high risk for disease with these agents by virtue of their age (the young and the old), their extent of exposure, or their host susceptibility, and hence special precautions for these groups are needed. The primary treatment of all these diseases is replacement of fluids and electrolytes. Prevention of the main childhood disease, rotavirus-induced diarrhea, rests with the recently introduced vaccines. Prevention of viral gastroenteritis epidemics will rest with the identification of the vehicle of infection, interruption of the mode of transmission, and the potential development of vaccines.

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• Chapter 5 : Viral Hepatitis

  Authors: Andrew W. Tai, Jules L. Dienstag
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    This chapter discusses the typical clinical and pathological features of viral hepatitis as well as the suggested initial evaluation of a patient presenting with suspected viral hepatitis. Five different human hepatitis viruses have been recognized and characterized in detail. The five established agents are hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV), all RNA viruses, except for HBV, a DNA virus. Two observations established that epidemics of jaundice were caused by a filterable infectious agent, i.e., a virus. First, outbreaks of hepatitis in military personnel immunized with yellow fever vaccine were shown to have resulted from contamination of the vaccine by an agent in the serum used to supplement viral culture media. Second, viral hepatitis was transmissible to volunteers with filtered inocula. The clinical features and course of uncomplicated acute viral hepatitis are similar among the several types of viral hepatitis. Fatigue, malaise, and anorexia are common symptoms and can accompany all types of chronic viral hepatitis. In uncomplicated acute viral hepatitis, the reticulin framework is typically preserved. Acute viral hepatitis may also result from infections other than HAV to HEV. HCV RNA testing may be useful if chronic viral hepatitis is suspected but other serologic markers (including anti-HCV) are negative, particularly in immunocompromised individuals or those on chronic hemodialysis.

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• Chapter 6 : Infections in Organ Transplant Recipients

  Author: John A. Zaia
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    Organ transplantation represents a continually expanding field of medicine, and with each innovative method for subverting the natural process of host immunity, new and unusual presentations for virus infections have occurred. With the increasing use of xenotransplantation, the concern about introducing viral zoonoses increases. But from a management standpoint, CMV, EBV, adenovirus (AV), and hepatitis virus infections consume a major focus of attention. However, certain unusual infections such as rabies, West Nile virus, and Creutzfeldt-Jakob disease (CJD) can be a concern after transplantation and are discussed in this chapter. Cytomegalovirus (CMV) produces disease principally in the immunologically impaired individual and, in doing so, demonstrates considerable variability in the types of clinical syndromes that are seen in different at-risk groups. In the transplant population, all aspects of the clinical manifestations of Epstein-Barr virus (EBV) infection can be seen, and for this reason, EBV is among the most important infectious problems after either hematopoietic cell transplantation (HCT) or solidorgan transplantation (SOT). The common respiratory virus infections, i.e., with respiratory syncytial virus, parainfluenza virus, influenza virus, and human metapneumovirus, occur in transplant patients, and except for the potential for serious pulmonary complications, the infections are not qualitatively different from those seen in otherwise healthy populations. The chapter also talks about adenovirus (AV) infection and herpesviruses.

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• Chapter 7 : Viral Myocarditis

  Author: Jeffrey A. Towbin
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    Myocarditis is an inflammatory process affecting the heart and causing ventricular dysfunction. In childhood, myocarditis is usually an acute process with left ventricular (LV) systolic dysfunction with or without dilation of the LV, while adult presentation is most typically chronic and mimics dilated cardiomyopathy (DCM) with LV dilation and systolic dysfunction or LV dysfunction without dilation. Usually sporadic, viral myocarditis can also occur as an epidemic. Viral infection triggers interstitial inflammation or myocardial injury, resulting in cardiac enlargement and an increase in the ventricular end-diastolic volume. Normally, this increase in volume results in an increased force of contraction, improved ejection fraction, and improved cardiac output as described by the Starling mechanism. In cases of chronic myocarditis, the valves may be glistening white, suggesting that endocardial fibroelastosis (EFE) may be the result of an in utero viral myocarditis. At the time of initial biopsy, a specimen may be classified as active myocarditis, borderline myocarditis, or no myocarditis, depending on whether an inflammatory infiltrate occurs in association with myocyte degeneration or necrosis (active) or too sparse of an infiltrate or no myocyte degeneration occurs (borderline). The current strategy for therapy includes supporting the blood pressure to achieve end-organ perfusion and urine output without "driving" the myocardium with inotropic agents.

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• Chapter 8 : Viral Infections of the Skin

  Authors: Brenda L. Bartlett, Stephen K. Tyring
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    A wide spectrum of skin lesions can result from viral infections. Three groups of viruses represent most primary epidermal viral replications: human papillomaviruses (HPV), herpesviruses, and poxviruses. Several virus families, such as retroviruses, paramyxoviruses, togaviruses, parvoviruses, and picornaviruses, produce skin lesions secondarily. Other viruses, such as rhabdoviruses, orthomyxoviruses, and reoviruses, rarely induce skin lesions. Viruses that infect the skin by direct inoculation include primary herpes simplex virus (HSV), papillomaviruses, and most poxviruses (except smallpox). Among rapid diagnostic tests, perhaps the most frequently used for detection of viral infections of the skin is fluorescent-antibody detection of HSV-1, HSV-2, and varicella-zoster virus (VZV). Maculopapular lesions may also be seen in erythema multiforme, which is common for viral etiology (HSV) or may be associated with nonviral infections or drug eruptions. Condyloma acuminatum must be differentiated from condyloma latum, the skin lesion associated with secondary syphilis. While a variety of enteroviruses, particularly coxsackieviruses, cause mucocutaneous manifestations, the two most distinctive clinical syndromes are hand-foot-and-mouth disease (HFMD) and herpangina. Rubella is an acute viral illness typically seen in children, although all age groups are susceptible. Human immunodeficiency virus (HIV) carries an RNA-dependent DNA polymerase, which allows viral RNA to be converted into a proviral DNA sequence. Enzyme-linked immunosorbent assay (ELISA) is used to screen for HIV infection while the Western blot assay is used to confirm the diagnosis.

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• Chapter 9 : Viral Hemorrhagic Fevers: a Comparative Appraisal

  Authors: Mike Bray, Karl M. Johnson
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    This chapter provides a general survey of viral hemorrhagic fever (VHF), comparing individual diseases to each other and to other types of human illness. The HF viruses belong to four different families, the Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. The various types of VHF have presumably occurred for millennia, whenever humans have come into contact with reservoir animals or been bitten by infected arthropods. The transmission of a virus from animals to humans can occur through direct physical contact, exposure to virus containing excretions, or the bite of an infected mosquito or tick. Lassa fever, among other things, is characterized by uncontrolled viral replication, in which the circulating viral titer correlates with the likelihood of death. The circulation of more than one serotype in the same geographic region sets the stage for the occurrence of secondary infections, in which nonneutralizing antibodies can enhance virus uptake into cells, causing intense inflammation and increased vascular permeability. At present, the best-understood form of VHF is the fulminant illness caused by Ebola Zaire virus, which displays all the classic features of the HF syndrome. The signs and symptoms of VHF resemble those of a wide range of infectious diseases, so a specific diagnosis can be made only by means of specialized laboratory tests that directly identify the pathogen. Considerable progress has been made in developing experimental vaccines for a number of types of VHF, based on a variety of platforms.

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• Chapter 10 : Viral Disease of the Eye

  Authors: Garry Shuttleworth, David Easty
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    The eye and its adnexal structures are subject to a number of viral diseases. The initial part of this chapter discusses anatomic and physiological considerations of the eye and its principal clinical syndromes. Ocular disorders are classified according to the affected anatomic structures, for the most part, for example, keratitis, uveitis, cataract, and retinitis. The latter part of this chapter discusses the eye's major viral diseases and highlights selected risk groups. The development of and advances in antiviral therapies have made many of the viral diseases of the eye amenable to treatment. Acute retinal necrosis (ARN) is most commonly caused by varicella-zoster virus (VZV) infection but it may also be caused by herpes simplex virus (HSV), cytomegalovirus (CMV), or Epstein-Barr virus (EBV) infection. The development of ARN may be related to an impairment of cell-mediated immunity. Ocular adenoviral infection results in an acute, self-limited disease that varies considerably in severity and typically affects children and young adults. As most infections with adenovirus are self-limited and resolve without sequelae, the only indications for corticosteroid use are cicatrizing conjunctival disease or visual compromise resulting from corneal cellular infiltrates or scarring.

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• Chapter 11 : Antiretroviral Agents

  Authors: Magdalena E. Sobieszczyk, Barbara S. Taylor, Scott M. Hammer
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    In 1987, zidovudine became the first approved agent in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Two decades later, 24 additional agents in six drug classes had been approved. These include nucleoside analog reverse transcriptase inhibitors (NRTIs), a nucleotide analog reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and an integrase inhibitor. This chapter describes the major characteristics of antiretroviral agents that are currently approved, or at a promising stage of development, and is organized according to the virus replication cycle. The current therapeutic niche of chemokine receptor 5 (CCR5) inhibitors is as one component of combination regimens for patients with multidrug-resistant R5 virus. In vitro, maraviroc demonstrates no antagonism with existing antiretroviral agents and additive or synergistic activity in combination with enfuvirtide. Vicriviroc is a potent inhibitor of most R5 viruses in vitro, with an IC50 in the range of 20 nM. It demonstrates additive or synergistic activity in combination with other approved antiretroviral agents. Additive or synergistic in vitro inhibition has been reported with double or triple combinations of numerous antiretroviral agents, except for zidovudine-stavudine, which is an antagonistic combination. Stavudine enjoys relatively few drug-drug interactions compared to other antiretroviral agents. The major mechanism of clearance of raltegravir in humans is by hepatic uridine diphosphoglucuronosyl transferase (UGT)-1A1. Amprenavir is additive with a number of other antiretroviral agents (zidovudine, didanosine, abacavir, saquinavir, indinavir, and ritonavir).

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• Chapter 12 : Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents

  Authors: Michael T. Yin, James C. M. Brust, Hong Van Tieu, Scott M. Hammer
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    This chapter reviews agents which have been, or are being, developed to treat herpesvirus, hepatitis virus, and respiratory virus infections. Detailed information is provided for approved agents and those in more advanced stages of clinical development. Agents in phase I human studies or promising approaches which are still in preclinical development are described briefly. The anti-herpes simplex virus (HSV) activity of acyclovir demonstrated that analogs of guanosine were active and that acyclic side chains could substitute for the ribose moiety, conferring specificity by the selective uptake and activation of acyclovir in HSV-infected cells. Thymidine kinase-deficient or -altered HSV or varicella-zoster virus (VZV) isolates resistant to acyclovir remain susceptible in vitro to foscarnet, cidofovir, and brivudine but are fully cross-resistant to ganciclovir and famciclovir. The more convenient dosing schedule of famciclovir and the potentially shorter duration of postherpetic neuralgia argue in favor of employing famciclovir or valacyclovir for herpes zoster, particularly in older individuals, in whom the complication of postherpetic neuralgia is more frequent. Cidofovir has been primarily developed as an anti-CMV agent but has broad antiherpesvirus activity. New antiherpesvirus drugs include inhibitors of immediate early gene expression, nonnucleoside DNA polymerase inhibitors, helicase-primase inhibitors, inhibitors of protein-protein interactions among DNA replication proteins, and inhibitors of assembly, encapsidation, and nuclear egress. The chapter describes agents that are primarily or exclusively directed at treatment of hepatitis virus infection. Antiviral activities of ribavirin are also described.

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• Chapter 13 : Diagnosis of Viral Infections*

  Authors: Guy Boivin, Tony Mazzulli, Martin Petric, Michel Couillard
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    The traditional epidemiological and academic reasons for diagnosis of viral infections have been expanded by rapid, often quantitative assays that can impact on therapeutic management and public health decisions. All methods used for viral isolation require living cells because viruses are obligate intracellular parasites. Historically, the systems used to isolate viruses of medical importance consisted of laboratory animals, embryonated eggs, and cultured cells. In the past two decades, safe and effective antiviral drugs have been developed for the treatment of many acute and chronic viral infections. In most diagnostic laboratories, electron microscopy (EM) for the diagnosis of viral infections has been supplanted by other methods, but EM remains an important and often rapid method for detecting viruses in clinical samples. Viral serologic assays contribute significantly to the indirect diagnosis of acute, recent, or chronic viral infections and are used widely for determining the immune status of a person or group of individuals with regard to a specific virus or to verify the immune response to vaccination. A variety of methods are available for serodiagnosis of viral infections. Failure to establish an accurate serologic diagnosis frequently results from the inability to submit an adequate pair of serum samples.

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• Chapter 14 : Immune Responses to Viruses

  Authors: Jonathan W. Yewdell, Theodore C. Pierson, Jack R. Bennink
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    The vertebrate immune system has evolved in response to the threat posed by viruses. A number of viruses have evolved gene products for subverting specific elements of the immune system. Nonspecific immune mechanisms can be triggered by cellular sensing of viral invasion, viral destruction of cells, recognition of infected cells by natural killer (NK) cells, or direct interaction of complement with virions. Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that are the source for most of the initial wave of type I interferons (IFNs) induced by many viruses. These cells reside in the T-cell regions of the spleen and lymph nodes and can be activated by noninfectious forms of viruses. Signals transduced through recognition of pattern recognition receptors (PRRs) at the onset of innate responses critically impact the development of adaptive immune responses. NK cells can directly interfere with viral reproduction by releasing cytokines with antiviral activity or by lysing virus-infected cells. Macrophages play a role in the destruction of antibodycoated virions, via Fc receptor-mediated internalization of immune complexes into lysosomes. The role of neutrophils in viral immunity is very poorly defined, even though neutrophils, like macrophages, are highly abundant phagocytic cells with Fc receptors and are recruited in large numbers to sites of viral infection. The most important result of T-cell receptor (TCR) stimulation of naive T cells is the increase in the transcription of interleukin-2 (IL-2) and the IL-2 receptor.

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• Chapter 15 : Immunization against Viral Diseases

  Authors: Julie E. Martin, Barney S. Graham
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    This chapter provides a review of the current viral vaccine practices and concepts, and indicates future directions for vaccine research and development. ‘‘Active immunization’’ to a virus can be induced through natural infection or by vaccination. ‘‘Passive immunization’’ refers to a transfer of temporary immunity to the host, and provides transient immune-mediated protection from infection or disease. Immunization can influence antibody-mediated immunity in many ways. First, by increasing the repertoire and the frequency of immunoglobulin receptors on memory B cells capable of recognizing a particular antigen, the kinetics of antibody production on subsequent exposure will be more rapid. Second, somatic hypermutation and B-cell selection result in antibodies of successively higher affinities, so repeated virus infection or immunization will cause affinity maturation. Third, immunization with a vaccine formulation that promotes IFN-γ production will increase the production of the immunoglobulin G1 (IgG1) and IgG3 subclasses. Finally, repeated immunization can improve the breadth of antibody responses to a particular virus by recruiting new responses to different antigenic regions. Many killed or inactivated and subunit viral vaccines have also been licensed for the prevention of viral diseases. The major advantage of inactivated vaccines is that there is no risk of infection in the vaccinated patient or of transmission of live virus to potentially immunocompromised close contacts of vaccinees. In general, the most effective way of protecting people with immunodeficiencies from vaccine-preventable diseases is to make sure the people around them are well vaccinated and are not transmitters of infection.

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• Chapter 16 : Gene Therapy and Viruses

  Authors: Donald B. Kohn, Barrie J. Carter, Paolo Grandi, Joseph C. Glorioso
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    Gene therapy is an emerging medical approach which seeks to apply molecular techniques to attack diseases at the fundamental level of the genes. The first techniques which were developed for genetic manipulation of mammalian cells involved direct introduction of genes in the forms of expression plasmids by physical methods. However, other gene therapy applications require stable persistence of the transferred gene in the target cells, so that the gene will be retained with each cell division and inherited by all progeny cells. The viruses which have been adapted and most widely studied for gene transfer include retroviruses, adenovirus (Ad), adeno-associated virus (AAV), herpesviruses, and, most recently, lentiviruses. Importantly, lentiviral vectors tolerate complex genetic elements better than retroviral vectors, possibly aided by the Rev/Rev response element-mediated mechanism for nuclear-to-cytoplasmic export of HIV-1 transcripts. Complement fixation (CF) appeared to be an attractive target for gene therapy, and extensive preclinical studies of the safety and toxicity of an AAV-CF transmembrane regulator (CFTR) vector were performed by delivery of vector particles directly to the lungs in rabbits and nonhuman primates. Importantly, sperm is generally negative for vector sequences, which diminishes the likelihood of modifying germ line cells. The use of viruses with improved initial intratumoral distribution and carrying genes that both overcome innate immune responses and promote an intra-cellular proapoptotic state should improve the potency of herpes simplex virus (HSV) cancer gene therapy vectors without compromising safety.

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• Chapter 17 : Chronic Fatigue and Postinfective Fatigue Syndromes

  Authors: Andrew R. Lloyd, Ian Hickie, Denis Wakefield
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    Chronic fatigue syndrome and postinfective fatigue syndrome have been the focus of considerable research interest, including epidemiological studies; investigations of microbiological, immunologic, neuroendocrine, metabolic, and psychological hypotheses of etiology; and treatment interventions. The most widely known predecessor to the current label of chronic fatigue syndrome is the disorder termed ‘‘neurasthenia,’’. The fatigue state was present from the time of onset of symptoms of the acute infection and was stable in character over time, suggesting that the genesis of the postinfective fatigue syndrome is intrinsically linked to the host-pathogen interactions in the acute infection phase. The fatigue syndrome was most prevalent in those with mononucleosis documented to be due to Epstein-Barr virus (EBV) infection and was shown to be essentially independent of psychiatric diagnoses. The modern era of research in relation to chronic fatigue syndrome has been marked by the formulation of diagnostic criteria. The Centers for Disease Control and Prevention then proposed the term chronic fatigue syndrome to replace numerous previous eponyms. Studies with patients with the overlapping clinical syndrome of fibromyalgia have demonstrated the benefit of a combination of a low-dose tricyclic antidepressant and a nonsteroidal anti-inflammatory agent, where effects on muscle pain and sleep disturbance are notable, arguing for a similar therapeutic trial in patients with chronic fatigue syndrome in whom pain and sleep disturbance are prominent.

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PART A DNA VIRUSES

• Chapter 18 : Poxviruses

  Authors: R. Mark Buller, Frank Fenner
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    Vaccinia virus (VACV) and cowpox virus (CPXV) are distinct orthopoxviruses that cause human infections, and one is not a synonym for the other. Poxvirus virions appear to be oval or brick-shaped structures of about 200 to 400 nm in length with axial ratios of 1.2 to 1.7. The structure of VACV is characteristic of that of all the poxviruses that infect humans except those belonging to the genus Parapoxvirus. In studies of human monkeypox carried out in Zaire between 1981 and 1986, twenty-seven of 136 (20%) persons gave no history of illness, residual skin lesions, or other changes suggestive of monkeypox, and therefore were classified as having subclinical infections. Human infections with bovine pustular stomatitis virus (BPSV) are less common than with the other two parapoxviruses that infect humans, probably because contact between animal handlers and lesions of BPSV are less common than those of shearers with orf and milkers with milker's nodules. The major diagnostic criteria for poxvirus infections are the size and morphology of the poxvirus virion in negatively stained preparations viewed with an electron microscope. Historically, antigen detection protocols rarely could differentiate poxviruses at the species level. Most importantly, Cidofovir (CDV) and hexadecyloxypropyl (HDP)-CDV have broad-spectrum activity against viruses that encode DNA polymerases, including all poxviruses known to infect humans, adenoviruses, and many herpesviruses. The effectiveness of the egress inhibitor ST-246 against poxviruses of other genera will depend on the importance of the cell-to-cell spread of virus in the disease process.

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• Chapter 19 : Herpes Simplex Viruses

  Authors: Richard J. Whitley, Bernard Roizman
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    Herpes simplex virus (HSV) infections of humans have been documented since the advent of writing. The spectrum of disease was expanded to include primary and recurrent infections of mucous membranes (gingivostomatitis, herpes labialis, and genital HSV infections), keratoconjunctivitis, neonatal HSV infection, visceral HSV infections of the immunocompromised host, HSV encephalitis, Kaposi's varicella-like eruption, and an association with erythema multiforme. Cumulative experience suggests that factors associated with pregnancy may place both the mother and fetus at increased risk for severe infection, possibly because of altered cell-mediated immunity. The major risk to the fetus is with primary or initial genital HSV infection of the mother. PCR evaluation of cerebrospinal fluid can be utilized to monitor therapeutic outcome in patients with herpes simplex encephalitis. The use of HSV for gene therapy heralds a new era of herpes biology, the conversion of a hazardous foe into a user-friendly surgical tool. Asymptomatic shedding of virus can continue despite clinically effective suppression with acyclovir, so the possibility of person-to-person transmission persists. Newborns with HSV infections can be classified as having disease that is localized to the skin, eyes, and mouth; affects the central nervous system (CNS); or is disseminated. Drug resistance was considered rare and resistant isolates were thought to be less pathogenic until a series of acyclovir-resistant HSV isolates from patients with AIDS were characterized. The risk of nephrotoxicity can be minimized by administering acyclovir by slow infusion and ensuring adequate hydration.

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• Chapter 20 : Cercopithecine Herpesvirus 1 (B Virus)

  Author: Richard J. Whitley
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    B Virus infection in macaques rarely causes disease, and if so, it is in the form of mild ulcerative lesions. B virus polypeptides and glycoproteins can be grouped into classes that differ in their relative rates of synthesis at different times throughout the virus replication cycle, as is characteristic of alphaherpesviruses. During the course of B virus infection, several observations are common to the natural host, the experimentally infected host, and infected humans. B virus is an infection that humans rarely contract, but when they do, 80% of untreated cases result in death. Observations of the clinical pattern of disease are important for rapid diagnosis of B virus infection in both macaques and humans. The neutralization antibody test was the predominant diagnostic tool in macaques and humans for many decades. Currently, the most effective assay for diagnosis of B virus in a nonmacaque is a competition enzyme-linked immunosorbent assay (ELISA) to facilitate discrimination between specific and cross-reactive antibodies, similar to the challenge faced when diagnosing infection in humans. Multiple levels of prevention are used to prevent B virus infection in both humans and nonhuman primates, ranging from attempts to eliminate virus from colonies to designing methods to work safely in environments where there is an increased risk for contracting the agent.

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• Chapter 21 : Varicella-Zoster Virus

  Authors: Anne A. Gershon, Saul J. Silverstein
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    Varicella-zoster virus (VZV) is the etiologic agent of two diseases, varicella (chickenpox) and zoster (shingles). Researchers performed the first successful in vitro studies and showed that viruses isolated from patients with varicella and zoster are immunologically similar. There are minor differences in DNA sequence among VZV isolates, and at least seven genotypes have now been identified, which on the basis of single nucleotide polymorphisms are classified as European, Japanese, or Mosaics. Cell-to-cell spread is thought to be the major means of spread of VZV in the body and would explain the importance of cellular immunity rather than antibodies in host defense against this virus. The other form of spread is by cell-free virus. There is little available information on the stability of VZV, but it is usually classified as a rather labile agent. Prevention of varicella may be accomplished with either active or passive immunization. In one study, about two-thirds of cases of breakthrough varicella were classified as mild. A recent study showed no difference in outcome in older patients with zoster whether they were treated with therapeutic oral acyclovir (ACV) for 7 or 21 days. In this study, recovery was no more rapid, nor was postherpetic neuralgia (PHN) less likely to occur, if a 3-week course of tapering prednisolone (beginning at 40 mg/day) was given along with ACV.

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• Chapter 22 : Cytomegalovirus

  Authors: Paul David Griffiths, Vincent Clive Emery, Richard Milne
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    Human cytomegalovirus (HCMV) was first isolated 50 years ago, when the new technology of cell culture became available. The pathogenesis of HCMV disease is complex, involving contributions from the host as well as from the virus. Increasing knowledge about the genetic composition of the virus can help to illuminate this complex series of relationships and provide a rational basis for therapeutic intervention and prevention of disease. The major immediate-early promoter (MIEP) enhancer contains multiple recognition sites for the transcription factors. Additionally, the MIEP is specifically transactivated by the tegument protein pp71, which is released as soon as incoming virions are uncoated. Thus, HCMV employs multiple methods independent of de novo viral gene expression to induce an intracellular milieu favorable to the initiation of immediate-early (IE) gene transcription. Humoral immunity could reduce the level of HCMV replication and reduce disease without being able to eliminate infection entirely. Humoral immune responses are directed against multiple CMV proteins, including surface glycoproteins, phosphoproteins of the tegument, and structural proteins of the capsid. Reverse transcription-PCR (RT-PCR) should detect only cells in which HCMV is replicating, since the target is mRNA. A nucleic acid sequence-based amplification NASBA assay for the detection of a late gene transcript (pp67) appears to be sensitive and specific and is available commercially.

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• Chapter 23 : Human Herpesvirus 6 and Human Herpesvirus 7

  Authors: Koichi Yamanishi, Yasuko Mori
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    Human herpesvirus 6 (HHV-6) was first isolated from patients with lymphoproliferative disorders in 1986 and was initially named human B-lymphotropic virus. Characterization of HHV-6 indicated that the virus is antigenically and genetically distinct from other known human herpesviruses. HHV-7 can be frequently isolated from saliva of healthy adults, and horizontal transmission of HHV-7 may occur even from grandparents or parents to children through close household contact. Thus, the modes of transmission of HHV-6 and -7 are very similar; however, it is not clear why HHV-7 infection occurs generally later than HHV-6 infection. Western blotting and immunofluorescent-antibody assay (IFA) demonstrated the presence of HHV-6 antibody in monkeys. HHV-6 DNA can be detected by DNA hybridization and by PCR. Variant-specific oligonucleotide hybridization is based on the amplification of two distinct regions of the HHV-6 genome, followed by hybridization of amplimers with variant-specific oligonucleotide probes. The primer sequences, based on consensus sequences in the DNA polymerase gene of herpesviruses, can be used for testing six different herpesviruses simultaneously. Comparison of the multiplex assay with the respective single PCR assays using cloned HHV-6 and HHV-7 sequences as targets for amplification demonstrated equivalent sensitivities and specificities of the assays. This multiplex assay is an efficient and cost-effective approach to the analysis of large numbers of samples to determine the epidemiological importance of HHV-6 and -7. Several serologic assays are available for HHV-6 studies, including IFA, enzyme-linked immunosorbent assay, neutralization, radioimmunoprecipitation, and immunoblotting.

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• Chapter 24 : Epstein-Barr Virus

  Authors: Katherine Luzuriaga, John L. Sullivan
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    Epstein-Barr virus (EBV) is a member of the Gammaherpesvirinae subfamily of the family Herpesviridae and is the prototype for the Lymphocryptovirus genus. Two types of EBV, EBV-1 and EBV-2, have been identified in most human populations. The major identified differences between the EBV-1 and EBV-2 genomes exist in the latent infection cycle nuclear antigen genes for EBV nuclear antigen 2 (EBNA-2); EBNA-LP; and EBNA-3A, -3B, and -3C and in the small, nonpolyadenylated RNA EBER-1 and -2. B lymphocytes are the primary cellular reservoir of EBV infection. The initial stage of infection involves a high-affinity interaction between the major EBV outer envelope glycoprotein, gp350, with CD21 on the surface of B cells. EBER genes are the most abundantly transcribed EBV genes in latently infected cells (104 to 105 copies/cell), distantly followed by the latent membrane protein 1 (LMP-1) gene, which, in turn, is significantly more abundant than the EBNA and LMP-2 genes. The EBV genes expressed during the late stages of lytic infection mostly encode structural viral proteins, which permit virion maintenance and egress. The viral glycoproteins are all encoded by late genes, which are of potential importance in antibody-mediated immunity to EBV. The recent demonstration that EBV can infect smooth-muscle cells in human immunodeficiency virus (HIV)-infected individuals may help explain the role of EBV in the pathogenesis of leiomyomas.

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• Chapter 25 : Kaposi’s Sarcoma-Associated Herpesvirus

  Authors: Patrick S. Moore, Yuan Chang
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    Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is a large double-stranded DNA herpesvirus that causes Kaposi’s sarcoma (KS) as well as some malignant and hyperplastic lymphoid disorders. KSHV also resides as a latent virus in infected cells. In contrast to lytic replication, latent viral gene expression provides proliferation and survival factors that inhibit premature cell death. Initiation of lytic replication begins with a highly choreographed cascade of gene expression that determines the sequence of events leading to linear genome replication, virion synthesis, genome packaging, and egress of the virus from the infected cell. Although the incidence of AIDS-associated KS declined 70 to 90% after the introduction of effective antiretroviral therapy, these drugs do not inhibit KSHV infection, and a second emergence of KS among persons with low HIV loads and high CD4+ cell counts has been reported. Although KSHV is poorly transmissible through transfusion, transfusion transmission can occur and may cause silent transmission and disease. Studies of AIDS patient cohorts show that KS can develop within weeks or months of primary infection, and in one case, an HIV-positive man developed transient angiolymphoid hyperplasia with microscopic foci of KS spindle cells immediately after infection. The majority of Castleman’s disease is of the hyaline-vascular variant, which presents as solitary lymph node hyperplasia typically in the mediastinum or retroperitoneum. Among AIDS patients, the most effective control measure for KS is effective antiretroviral therapy. The rate of new KS diagnoses is markedly lower among persons on highly effective antiretroviral therapy.

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• Chapter 26 : Adenoviruses

  Authors: Olli Ruuskanen, Jordan P. Metcalf, Olli Meurman, Göran Akusjärvi
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    The human adenoviruses comprise 51 distinct serotypes that are grouped into six subgroups (A to F) based on various immunologic, biological, and biochemical characteristics. The infection cycle takes approximately 30 h in tissue culture cells and results in the production of approximately 50,000 to 100,000 new virus particles per cell. The infectious cycle can be divided into four stages: entry, early events, late events, and virus assembly. Chloramine-T (p-toluenesulfonchloramide) at 5% for 15 min or at 0.6% for 30 min or 500 ppm of sodium hypochlorite for 10 min can be used to inactivate adenoviruses. Phenylmercuric borate, isopropyl alcohol, ether, cetrimide, and chlorhexidine gluconate do not inactivate adenoviruses. Approximately 10 to 20% of childhood pneumonias are attributed to adenoviruses. Adenoviral pneumonia in military conscripts was originally classified as atypical pneumonia until the viral etiology was discovered. Clinically and radiologically adenoviral pneumonia may resemble Mycoplasma pneumoniae pneumonia. Recent observations on detection of adenoviruses by PCR in air and on surfaces suggest that proper cleaning, isolation of patients with suspected or confirmed cases of adenovirus infection, and restriction of new admissions may be essential in limiting the risk of nosocomial spread. At present there is no specific antiviral treatment of proven value for adenovirus infections. Ribavirin, ganciclovir, and cidofovir are variably active against adenoviruses in vitro and thus potentially effective for treatment.

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• Chapter 27 : Polyomaviruses

  Authors: John E. Greenlee, Frank J. O’Neill
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    Polyomaviruses are widely distributed in humans and other animal species. Polyomaviruses were initially considered a genus within the family Papovaviridae, which included papillomaviruses and polyomaviruses. Simian virus 40 (SV40) produces renal involvement in its simian host, as do JC virus (JCV) and BK virus (BKV) in humans. The major known site of BKV persistence is the renal tubular epithelium, and persistent infection of renal tubular epithelium cells, like that seen with JCV and with mouse pneumotropic virus (MPtV), appears to involve not a state of viral latency but rather ongoing productive infection at low level. Those which predispose to progressive multifocal leukoencephalopathy (PML) are not fully understood. A group of investigators has attempted to duplicate PCR isolation of polyomaviruses from the same tumor material in different laboratories. In this study, PCR analysis of the same 225 brain tumor samples was carried out in two geographically separated laboratories. Earlier, the use of PCR analysis of cerebrospinal fluid (CSF) enabled specific diagnosis in 80 to 90% of cases. Highly active antiretroviral therapy (HAART) has been shown to reduce viral load of JCV in CSF, however, and while CSF PCR remains a valuable diagnostic tool in this setting, the diagnostic yield in patients treated with HAART has been shown to be reduced to 57.5%. Recently, based on the observation that JCV binds to the serotonin receptor, one study reported stabilization of disease and improvement in PML lesions following treatment with the serotonin reuptake inhibitor, mirtazapine.

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• Chapter 28 : Papillomavirus

  Author: William Bonnez
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    Human papillomaviruses (HPVs) primarily infect the stratified squamous epithelia of humans. Papillomavirus genotypes are classified as distinct if their genomes have less than 90% homology in the DNA sequences of the L1 open reading frame (ORF), which encodes the major capsid protein. The study of papillomavirus L1 VLPs has shown that serotypes generally correspond to genotypes. Papillomavirus genomes share the same general organization, which usually consists of eight ORFs, all located on the same strand. Three major types of cutaneous warts are recognized: deep plantar warts, common warts, and flat or plane warts. Screening strategies for anal cancer based on anal cytology have been proposed. Present therapeutic options are directed at eradicating the disease, not the infection, by destroying the lesions with physical or chemical means or by stimulating an inflammatory or immune response. A majority of these treatments have been developed empirically, but few have been thoroughly tested, and none is completely satisfactory. A section reviews the most commonly used and best-evaluated forms of treatment for HPV diseases. The current HPV VLP vaccine has not shown any therapeutic effect. Photodynamic laser therapy is an evolving and successful approach for the treatment of cutaneous warts, genital HPV diseases, and recurrent respiratory papillomatosis. The simplest and most effective office-based treatment modalities are cryotherapy and trichloroacetic acid (TCA) application. Cryotherapy, TCA application, electrosurgery, coldblade excision, and laser surgery are all appropriate for the treatment of condyloma acuminatum in the pregnant patient.

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• Chapter 29 : Human Parvoviruses

  Authors: Larry J. Anderson, Dean D. Erdman
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    The family Parvoviridae is divided into two subfamilies: the Densovirinae, which infect insects, and the Parvovirinae, which infect vertebrates. The members of the Parvovirinae that infect humans are the focus of this chapter. The parvoviruses known to infect humans include B19 parvovirus in the genus Erythrovirus, adeno-associated viruses (AAVs) in the genus Dependovirus, human bocavirus (HBoV) in the genus Bocavirus, and PARV4 and PARV5, not yet placed into a genus. With the appropriate helper virus, AAVs can replicate in a variety of tissue culture systems. If a helper virus is not present, AAV integrates into the host cell genomic DNA in a site-specific fashion. Nosocomial transmission can, however, occur, and standard precautions are recommended for all B19-infected patients and droplet precautions are recommended for those most likely to have high-titer infection, i.e., those with chronic B19 infection and those with transient aplastic crisis. The occurrence of rash in an immunocompromised patient after treatment with immune globulin and again after the patient mounts an antibody response suggests that anti-B19 antibody is important to the pathogenesis of the rash. The majority of recent studies of AAVs and studies of PARV4 and PARV5 and HBoV have been based on a variety of PCR assays to detect the viral DNA. A serologic assay for HBoV has recently been described based on cloned expressed capsid proteins forming empty capsids.

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• Chapter 30 : TT Virus

  Author: Peter Simmonds
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    TT virus (TTV) and its relatives are small nonenveloped viruses with circular single-stranded DNA genomes. Infections are characterized by their lifelong persistence and their great genetic variability. The cloning of the newly christened TT virus provided nucleotide sequences that allowed the development of methods for its detection by PCR. Although the genome organization of TTV and its relatives shows similarities to that of chicken anemia virus (CAV), the latter virus remains classified as the type member of the Gyrovirus genus within the virus family Circoviridae. TTV and TTV-like minivirus (TTMV) are likely to replicate in the nucleus of the infected cell, using host polymerases. The replication of small DNA viruses such as the parvoviruses is cell cycle dependent, and their replication is confined to rapidly dividing cells, such as those in the bone marrow, the gut, and fetal tissue. PCR is the principal method used for the detection of TTV DNA in clinical specimens. Methods that use heminested or fully nested primers are capable of extremely high sensitivity and specificity. The untranslated region (UTR) of TTV is much more conserved than the coding region and therefore more appropriate as a target sequence for PCR. As infection with TTV and/or related viruses is universal, measures to prevent transmission are unwarranted. Similarly, there is no current indication to treat individuals infected with TTV.

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• Chapter 31 : Hepatitis B Virus

  Authors: Alexander J. V. Thompson, Sally J. Bell, Stephen A. Locarnini
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    The goal of chemoprevention for chronic hepatitis B (CHB) must be to improve the quality and the outcomes of care for patients with CHB. This chapter focuses on the human hepatitis B virus (HBV). HBV is an enveloped, 3.2-kb double-stranded DNA virus which may be classified into eight major genotypes (A to H) based on a nucleotide diversity of 8% or more. HBV infection is usually diagnosed using specific serologic assays. During the course of infection, the viral proteins HBsAg, HBcAg, and HBeAg stimulate the immune system to produce the corresponding antibodies anti-HBs, anti-HBc, and anti-HBe. Once HBV DNA becomes detectable, replication increases exponentially to peak at levels of >1012 copies/ml in serum. In adult-acquired acute HBV infection, in which the host is able to control the virus, viral replication then declines, preceding the onset of clinical hepatitis. The risk of fulminant hepatic failure (FHF) may be higher in patients acutely infected with basal core promoter (BCP) or precore variants, coinfected with other hepatitis viruses, or with underlying liver disease. The major complications of CHB are cirrhosis, hepatic decompensation, and HCC. The current challenge in CHB is to identify patients at risk for progressive liver disease, so that therapy may be offered early to alter the natural history. The major risk factors for progression to cirrhosis are viral load, the presence of fibrosis on liver biopsy, and elevated serum alanine aminotransferase (ALT).

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PART B RNA VIRUSES

• Chapter 32 : Human Lymphotropic Viruses: HTLV-1 and HTLV-2

  Authors: William A. Blattner, Manhattan E. Charurat
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    The discovery of the human T-cell lymphotropic virus type 1 (HTLV-1), in 1979 ushered in a new age of medical virology. The association of HTLV-1 with adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), as well as other diseases, was established by clinical epidemiological studies, whereas links of human T-cell lymphotropic virus type 2 (HTLV-2) to diseases are less certain. Major structural and regulatory proteins of HTLV-1 are summarized in this chapter. The current standard of care involves antibody screening of donors and, if needed because of in-determinant Western blot results, molecular screening is also performed, an algorithm that has eliminated transplant-associated transmission. At the center of disease pathogenesis are the gene products of the pX reading frame which not only are engaged in promoting viral replication but also impact cellular functions that favor viral replication. The most important of these viral gene products coded for by pX IV is the p40 Tax viral regulatory protein, which, like its counterpart Tat from human immunodeficiency virus type 1 (HIV-1), plays an important role in promoting viral growth and disease pathogenesis. Tax represses transcription of the Bax gene, the product of which accelerates apoptosis. The Lymphoma Study Group in Japan has classified ATL into four clinical types based on clinical features and cell morphology: acute, chronic, smoldering, and lymphoma/leukemia types. Refinements of the PCR assay resulted in a highly sensitive and reproducible detection system with limits of detection at 10 molecules of DNA in 1 mg of human DNA.

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• Chapter 33 : Human Immunodeficiency Virus

  Authors: John C. Guatelli, Robert F. Siliciano, Daniel R. Kuritzkes, Douglas D. Richman
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    The current designations of specific human immunodeficiency virus (HIV)-1 strains as circulating recombinant form (CRF) versus parental subtypes are subject to change, since putative evolutionary relationships can be confounded by sampling history and high rates of recombination. Disorders of the peripheral nervous system can be classified as distal symmetric polyneuropathy, toxic neuropathy, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, and mononeuropathy multiplex. The major causes of transmission of HIV, sexual intercourse and injection drug use, represent two extremely strong biological drives. The ultimate goal of chemotherapy of HIV is to thus identify drug regimens that completely inhibit virus replication. Although any function in a genetically efficient organism is a candidate for an inhibitory drug, the currently approved drugs are directed against reverse transcriptase (RT), protease (PR), integrase (IN), and viral entry, with the RT inhibitors being classified as nucleosides or nonnucleosides. The correlation of risk of progression with certain class I human leukocyte antigen (HLA) haplotypes and with the breadth and magnitude of cell-mediated immune responses has prompted interest in therapeutic immunization to enhance these beneficial responses. This approach in general has been aimed at delivering immunogens while the immune system is fully protected by potent antiretroviral chemotherapy and then ascertaining whether a benefit can be discerned after withdrawal of therapy.

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• Chapter 34 : Colorado Tick Fever Virus and Other Arthropod-Borne Reoviridae

  Authors: Steven Yukl, Joseph K. Wong
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    The development of viral cultures in chicken embryos and mice by Koprowski and Cox in the 1940s and subsequent refinements in viral isolation and molecular biology permitted further description of Colorado tick fever virus (CTFV). Much is now known about its ecological niche and life cycle in vertebrate and invertebrate hosts as well as the epidemiology, pathogenesis, and clinical course of infection in humans. The current taxonomy recognizes three distinct species: (i) the type species, Banna virus (BAV); (ii) Kadipiro virus; and (iii) Liao Ning virus. The pathogenic potential of these viruses in humans remains to be determined, although associations of BAV infection with febrile illnesses and encephalitis are convincing. Seadornaviruses are serologically distinct from CTFV and Eyach virus (EYAV), have a lower G+C content than coltiviruses, and show genetic distances in the RNA-dependent RNA polymerase of more than 90% compared to coltiviruses. The genome of all members of the Reoviridae consists of segmented double-stranded RNA (dsRNA). Electron microscopic (EM) studies of cultured cells following infection reveal viral particles in association with granular matrices within the cytoplasm. The name Orbivirus derives from the appearance of virus particles as large, doughnut-shaped capsomeres by negative-contrast EM. Though the most-studied orbiviruses are agents of veterinary import, a number of serogroups within the genus cause human disease. They are predominantly transmitted by arthropod vectors.

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• Chapter 35 : Rotaviruses

  Authors: Manuel A. Franco, Harry B. Greenberg
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    Rotaviruses belong to the Reoviridae family of icosahedral, nonenveloped, segmented double-stranded RNA (dsRNA) viruses. They are classified into groups (A through E) depending on the presence of cross-reactive epitopes primarily located on the internal structural protein VP6. This chapter mainly talks about group A rotaviruses. It presents details that include epidemiology, clinical manifestations, laboratory diagnosis, prevention and treatment of rotaviruses. Seroprevalence of antibodies for these rotaviruses is relatively high in humans, specially those living in rural areas, suggesting transmission from animals to humans. In humans, the capacity for rotaviruses to reassort influences the generation of serotypic diversity less dramatically than for influenza virus, although reassortment clearly occurs, especially in less developed countries. Rotaviruses have been proposed to enter cells by endocytosis and by direct plasma membrane penetration. Although symptomatic reinfection with rotaviruses seems to be frequent, the severity and number of rotavirus infections diminish with the age of the child, and severe infections seem to be primarily limited to the initial infection. Studies with mice have shown that rotaviruses are inactivated in the stomachs of adult but not newborn mice, which suggests that the development of gastric acid and pepsin secretion may be an important factor in host defense against rotavirus. The relative importance of transplacentally acquired versus breast-feeding-acquired antibodies in protection against rotaviruses in children is not clear. Precaution should be exercised in disinfection of surfaces thought to be contaminated with rotavirus, since rotaviruses have been shown to be highly resistant to many commonly used disinfectants.

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• Chapter 36 : Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Viruses

  Authors: John V. Williams, Pedro A. Piedra, Janet A. Englund
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    Respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and the parainfluenza viruses (PIVs) are the most important causes of lower respiratory tract illnesses in infants and children. RSV comprises of two heterotypic strains of viruses that are antigenically distinct, classified as subgroups A and B. The major difference between these subgroups is the antigenic properties of the G surface glycoprotein protein. Immune responses to the two PIV surface glycoproteins, hemagglutininneuraminidase (HN) and fusion (F), also appear to correlate with protection against infection. Importantly, respiratory diseases remain the most significant cause of mortality in young children worldwide, with an estimated 3 million to 4 million children under 5 years of age dying annually. RSV, PIV, and hMPV are the most important causes of lower respiratory tract disease in children. All these viruses spread primarily from cell to cell in the upper respiratory tract and at times progress to the lower respiratory tract. The inoculum size is an important variable for achieving RSV and PIV infections in adults and possibly infants and children. In lung transplant recipients infected with hMPV, both acute and organizing lung injury occur, with diffuse alveolar damage and cytoplasmic inclusion bodies. The majority of children infected with hMPV can be managed at home with supportive care. For infants and children who require hospitalization, therapy is supportive, including supplementary oxygen and intravenous hydration.

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• Chapter 37 : Measles Virus

  Authors: William J. Moss, Diane E. Griffin
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    Measles is one of the most important infectious diseases of humans and has caused millions of deaths since its emergence thousands of years ago. Measles virus (MV) is one of the most highly contagious infectious pathogens, and measles outbreaks can occur in populations in which fewer than 10% of persons are susceptible. Infection of the endothelial cells of small vessels in the lamina propria and dermis during the secondary viremia precedes infection of the overlying epithelium, and inflammatory changes in and around these vessels are an integral part of the local pathology and characteristic rash. MV-specific immune responses are essential for recovery from measles and for the establishment of long-term immunity to disease, but they also play a role in the pathogenesis of measles and its complications. Acute postinfectious measles encephalomyelitis is the most common neurologic complication of measles. A second form of measles encephalitis, subacute sclerosing panencephalitis (SSPE), is a rare delayed complication of measles that occurs in approximately 1 in 10,000 cases. The third form of measles encephalitis, measles inclusion body encephalitis (MIBE), is a progressive, generally fatal MV infection of the brain that occurs in immunocompromised patients. Different goals for measles control have been established, necessitating different vaccination strategies. Three broad goals can be defined: mortality reduction, regional elimination, and global eradication. Vitamin A is effective for the treatment of measles, and its administration has resulted in marked reductions in morbidity and mortality in hospitalized children with measles.

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• Chapter 38 : Mumps Virus

  Author: John W. Gnann, Jr.
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    Mumps virus is classified as a member of the order Mononegavirales, family Paramyxoviridae, subfamily Paramyxovirinae, and genus Rubulavirus. Penetration of mumps virus virions into target cells begins with binding of the hemagglutininneuraminidase (HN) surface glycoprotein to sialic acid-containing receptors on the cell surface. Humans can be experimentally infected by inoculation of mumps virus onto the nasal or buccal mucosa, suggesting that natural infection results from airborne spread of droplets of respiratory secretions from infected to susceptible individuals. Mumps virus can establish persistent infection in neuronal cell lines and chronic central nervous system (CNS) infection in animal models, but it does not routinely cause chronic infections in humans. In the suckling hamster model, mumps virus CNS infection is associated with the development of stenosis of the sylvian aqueduct and with granular ependymitis. The majority of mumps patients with CNS involvement will have signs of meningeal irritation but no evidence of cortical dysfunction. The pathogenesis of mumps-related arthritis is uncertain; virus has not been isolated from joint fluid, and there is no evidence of immune complex deposition. Although clinical experience with this assay is currently limited, reverse transcriptase (RT)-PCR is likely to become the diagnostic method of choice for mumps virus CNS infection. Therapy of patients with uncomplicated mumps consists of conservative measures to provide symptomatic relief, such as analgesics, antipyretics, rest, and hydration. Symptomatic measures to alleviate the pain and swelling of mumps orchitis include bed rest, scrotal support and opioid analgesics.

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• Chapter 39 : Zoonotic Paramyxoviruses

  Authors: Paul A. Rota, Thomas G. Ksiazek, William J. Bellini
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    This chapter focuses on recently emergent paramyxoviruses that are associated with zoonotic disease, Hendra virus (HeV), Nipah virus (NiV), and Menangle virus (MeV). Molecular biological studies have made substantial contributions to the characterization of recently emergent zoonotic paramyxoviruses. As for other paramyxoviruses, the NiV surface glycoproteins are the primary targets for neutralizing antibodies. The conservation of most of the structurally important amino acids suggests that the attachment proteins of HeV and NiV would have structures that are very similar to the structure proposed for the attachment proteins of other paramyxoviruses. The development or characterization of animal models to study henipavirus infections is critical for understanding their pathogenesis and for development of therapeutics or vaccines. The chapter describes the pathogenesis and immune responses of human infections for each virus. Traditional techniques of virus isolation in cell culture, electron microscopy, enzyme-linked immunosorbent assay-based serology, neutralization assays, and immunohistochemical (IHC) techniques have been employed in the diagnosis of the zoonotic paramyxoviruses. NiV and HeV are internationally classified as biosafety level or biosecurity level 4 (BSL-4) agents; thus, clinical specimens suspected to be infected with these agents must be handled with caution. Pig farmers in areas in which NiV may be endemic should be educated regarding the features of Nipah encephalitis in pigs and to report any unusual disease. Since transmission is possible without close contact with pigs, exposure to potentially infected animals should be completely avoided, if possible. Persons handling pigs or their excreta should wear protective equipment such as gloves and masks.

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• Chapter 40 : Rhabdoviruses

  Authors: Thomas P. Bleck, Charles E. Rupprecht
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    Rabies virus stands apart as the most uniformly fatal of all viruses and remains one of the most common viral causes of mortality in the developing world. Much of the basic virology of the rhabdoviruses has been elucidated by studies of vesiculoviruses. The epidemiology of human rabies primarily reflects that of animal rabies in the community. Cases of animal rabies throughout the world can be separated into two groups. In the developing world, rabies is predominantly a problem of domestic animals, with a smaller contribution from wild animals. In the more developed nations, animal control procedures have largely eliminated rabies from domestic animals, and wild animals are the major groups affected. The human immune response to natural rabies virus infection is insufficient to prevent disease. Human rabies virus infections are typically divided into two forms: furious and paralytic (or dumb). Furious rabies patients who receive maximal intensive care support and survive for a longer-than expected period appear to pass in the paralytic phase prior to death. Any levels in cerebrospinal fluid (CSF) are diagnostically valuable; this is true even for patients who have received postexposure prophylaxis. The currently employed human vaccines in the United States include human diploid cell vaccine (HDCV) and purified chicken embryo vaccine (PCEC). These vaccines are remarkably safe and immunogenic.

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• Chapter 41 : Filoviruses

  Author: Mike Bray
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    The two genera of filoviruses, Marburgvirus and Ebolavirus, are certainly the most virulent, and are possibly the most mysterious, of the viral pathogens that afflict humans. Person-to-person transmission occurs almost exclusively through direct contact with virus-containing body fluids, and there is no evidence of spread by insect vectors or the respiratory route. The major filoviral matrix protein, VP40, the most abundant protein in the virion, is the driving force behind the assembly and release of new viral particles from infected cells. Both Marburg and Ebola viruses have been recovered from wild African primates, but it is clear that those animals cannot serve as maintenance hosts, because their populations are too small to support the spread of a rapidly lethal disease. Instead, it appears likely that the filoviruses persist through continuous transmission in one or more species of small animals that are widely distributed in central Africa. Filoviruses replicate to high titers in many types of cultured cells, including Vero monkey kidney cells, human umbilical vein endothelial cells, and primary human macrophages. Cultured human macrophages infected with Ebola Zaire virus release the proinflammatory cytokines and chemokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, alpha interferon (IFN-1α), and RANTES into the growth medium. Reverse transcription-PCR (RT-PCR) has been found to be more sensitive than antigen-based tests for rapid diagnosis; in the Gulu epidemic, the technique identified infected patients 24 to 48 h earlier than an enzyme-linked immunosorbent assay (ELISA) method.

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• Chapter 42 : Influenza Virus

  Authors: Frederick G. Hayden, Peter Palese
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    Homologous recombination between corresponding RNA segments of different influenza viruses has not been observed, in contrast to the high frequency of recombination observed among the genomes of positive-sense RNA viruses, like polioviruses, and retroviruses. The virulence and host range of influenza viruses relate to the surface glycoproteins, as well as to other viral proteins. Zoonotic influenza virus infections are also spread by these routes through direct and indirect exposures and perhaps rarely by gastrointestinal infection. Influenza virus RNA is readily detected on fomites, and virus retains infectiousness longer on hard, nonporous surfaces, in low humidity, and at cooler temperatures, but the importance of transmission via fomites is unclear. Pathogenicity and cell tropism of influenza viruses relate in part to the hemagglutinin (HA) cleavability by particular host cell enzymes. Serine proteases, presumably derived from host epithelial cells, cleave the HA precursor molecule into HA1 and HA2 to render human influenza viruses infectious. Currently, use of inactivated influenza vaccine is the most important measure for reducing influenza virus-related morbidity and mortality. Drug recipients may experience subclinical infection, which usually confers protection against infection by the same strain. As antiviral chemoprophylaxis does not interfere with the immune response to inactivated vaccine, they can be administered concurrently. However, concurrent use of any anti-influenza antiviral drug might interfere with the immunogenicity of live attenuated influenza virus vaccines (LAIV).

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• Chapter 43 : Bunyaviridae: Bunyaviruses, Phleboviruses, Nairoviruses, and Hantaviruses

  Author: Gregory J. Mertz
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    The family Bunyaviridae is the largest family of animal viruses and includes many viruses that are known human pathogens. The clinical diseases produced in humans range from acute febrile illnesses, such as sandfly fever, to more distinct clinical syndromes such as California encephalitis (CE), Rift Valley fever (RVF), Crimean-Congo hemorrhagic fever (CCHF), hemorrhagic fever with renal syndrome (HFRS), and the recently recognized hantavirus cardiopulmonary syndrome (HCPS), which is also referred to as hantavirus pulmonary syndrome. Representative groups and complexes for the bunyaviruses, phleboviruses, and nairoviruses, including major human pathogens, are discussed. The limited host range and similar phylogenetic relationships among hantaviruses and among the rodent hosts have led to the suggestion that hantaviruses may have coevolved with their rodent hosts. Although infection with the hantaviruses causing HFRS occurs in all age groups, infection and disease peak in adults 15 to 40 years of age; like HCPS, HFRS is uncommon in children. The role of viremia in the pathogenesis of HFRS and HCPS is not known, but there is emerging evidence that viremia with ANDV routinely precedes the onset of symptoms and development of antihantavirus antibodies in HCPS by periods of up to 15 days. In eastern Asia, infection with Hantaan and Seoul hantaviruses is usually diagnosed serologically with immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), or bead agglutination formats, and IgM antibody is determined by IgM capture ELISA. Investigational strategies include DNA vaccination for pathogenic hantaviruses, including Hantaan virus and ADNV.

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• Chapter 44 : Arenaviruses

  Author: C. J. Peters
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    Arenaviruses are negative-stranded RNA viruses that cause chronic infections of rodents and zoonotically acquired diseases in humans. Other arenaviruses known from South America and Africa are common causes of the viral hemorrhagic fever (HF) syndrome in the areas in which they occur naturally. lymphocytic choriomeningitis virus (LCMV), Lassa virus, and other African arenaviruses compose the Old World arenaviruses, and the viruses from North and South America are referred to as the New World, American, or Tacaribe arenavirus serologic complex. The best-studied example of adaptation by arenaviruses is the work with variants of LCMV that can be isolated from different organs of neonatally infected mice. There are now several examples of chronic infections of laboratory rodents in which arenaviruses affect critical enzyme or hormone synthesis without morphological lesions being apparent. The major differences between the pathogenesis of Lassa fever and that of the South American HFs are quantitative rather than qualitative. The differential diagnosis may include early stages of human immunodeficiency virus infection, measles, hepatitis, infectious mononucleosis, collagen vascular diseases, and early stages of nephritis. The value of oral or intravenous ribavirin in prophylaxis of exposures to Lassa virus and other arenaviruses is uncertain, in part as neither the dose nor the duration for humans is established. Several additional candidate drugs with activity against arenavirus have been identified by in vitro screening, and others are being discovered through the intensive interest generated by biodefense programs.

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• Chapter 45 : Enteroviruses

  Author: José R. Romero
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    The original taxonomic classification of the enteroviruses (EVs) recognized 64 prototype serotypes within the family Picornaviridae. The majority of what is known about the pathogenesis of EV infections in humans has been based on the study of the polioviruses, the prototypic members of the genus, in experimental infections using chimpanzees more than four decades ago and, most recently, from transgenic mice expressing the poliovirus receptor CD155. The study of cell-mediated immune responses to EVs has been much more limited, and the importance of the cellular response in preventing or clearing infection is still unclear. A 20-year evaluation of the epidemiology of neonatal EV infections identified case fatality rates that ranged from approximately 17 to 20% for infants <1 month of age infected with echoviruses 6, 11, 20, and 30 and coxsackievirus B4. The clinical manifestations of EV-associated upper respiratory infections (URIs), otitis media, wheezing, and pharyngotonsillitis are indistinguishable from those due to other respiratory viruses. Although it is the most sensitive method for laboratory diagnosis of some coxsackievirus A infections, isolation of EVs in suckling mice is rarely performed any longer because of the difficulties of the technique and of animal maintenance. As with other viral pathogens, there are several steps in the replication cycle of the picornaviruses that are potential targets in antiviral therapy. Cell susceptibility, viral attachment, viral uncoating, viral RNA replication, and viral protein synthesis have all been studied as targets of antipicornaviral compounds.

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• Chapter 46 : Rhinovirus

  Authors: Ronald B. Turner, Wai-Ming Lee
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    Human rhinoviruses (HRVs) constitute the largest genus in the Picornaviridae family. In addition, rapid progress has been made in understanding the clinical characteristics and epidemiology of the rhinoviruses. Phylogenetic analysis of these sequences showed that 100 rhinovirus serotypes are divided into two genetic groups or species and that HRV87 is an enterovirus (enterovirus 68). The rhinovirus genome, like that of polio virus, is organized into three major regions based on proteolytic processing: P1, P2, and P3, representing genes for precursor proteins. An impressive feature of rhinovirus pathogenesis is that the nonspecific defense mechanisms of the nose are unable to prevent infection in the nonimmune individual and may, in fact, contribute to the pathogenesis of rhinovirus-associated illness. The major clinical syndrome associated with rhinovirus infection is rhinosinusitis, which is traditionally characterized as “the common cold”. Two clinical presentations of acute bacterial sinusitis can be recognized. First, the classical features of acute bacterial sinusitis include fever and facial pain, swelling, or tenderness. The current treatment of rhinovirus-associated illness relies on remedies directed at specific symptoms. The second and more common presentation of acute bacterial sinusitis is that of an acute respiratory illness which begins as a cold or ‘‘flu’’ but lasts longer than expected. Antiviral chemoprophylaxis for rhinovirus colds may have practical value, but no commercial product of proven efficacy is available. Alpha interferon applied topically in the nose is effective in reducing the incidence of colds in persons who are exposed to a family member with a fresh cold.

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• Chapter 47 : Hepatitis A Virus

  Authors: Philip R. Spradling, Annette Martin, Stephen M. Feinstone
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    Hepatitis A is an acute, self-limiting infection of the liver by an enterically transmitted picornavirus, hepatitis A virus (HAV). The genetic diversity of HAV has been investigated by determining the partial genomic nucleotide sequences of numerous human HAV strains recovered from various human or simian sources and geographic areas. Antigenic variants of HAV that resist neutralization by neutralizing monoclonal antibodies have been selected in cell culture by continued passage of cell culture-adapted virus in the presence of these antibodies. The marked effectiveness of universal early childhood vaccination has been described in settings where the prevaccine-era hepatitis A incidence was moderately high. Since the licensure of hepatitis A vaccine and the implementation of a national childhood immunization strategy, hepatitis A rates in the United States have fallen dramatically. Host factors reportedly associated with an increased risk of fulminant hepatitis include old age and underlying chronic liver disease. Prolonged jaundice in hepatitis A, often associated with fever and pruritus, is an indication of cholestatic hepatitis. Therefore, decisions to use vaccine or immune globulin (IG) should take into account the potential for severe manifestations of hepatitis A, including patient age and the presence of chronic liver disease. Screening of contacts for immunity before administering postexposure prophylaxis is not recommended because screening would result in delay.

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• Chapter 48 : Human Caliciviruses

  Authors: Robert L. Atmar, Mary K. Estes
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    Molecular cloning and characterization of the norwalk virus (NV) genome allowed this virus to be classified as a member of the family Caliciviridae. Although structural studies confirm that NV contains cup-shaped depressions, these depressions are often clearer in other strains of animal caliciviruses and human caliciviruses (HuCVs). Consistent with the fact that chemical agents are the most important cause of food-borne and waterborne disease, NV is resistant to inactivation following treatment with chlorine concentrations usually present in drinking water, and NV is more resistant to inactivation by chlorine than poliovirus 1, human rotavirus (Wa), simian rotavirus (SA11), or f2 bacteriophage. The cloning and expression of the NV genome resulted in the development of new assays and reagents that permit large-scale epidemiological studies. Much of the understanding of the epidemiology of noroviruses (NoVs) has come from studying the cause of outbreaks of water-borne and food-borne gastroenteritis. The first immunologic assays developed to detect antigen and amenable to large-scale use were radioimmunoassays (RIAs) and, subsequently, enzyme immunoassays (EIAs). Additional antigen detection EIAs were developed using other NoV and sapovirus (SaV) recombinant viruslike particles (rVLPs) as antigens for production of hyperimmune antisera. A number of different primer pairs and different reverse transcriptase PCR (RT-PCR) conditions have been described for the detection of NoVs and sapoviruses (SaVs). Serologic assays are used to determine the presence of virus-specific immunoglobulin M (IgM) in individual sera or rising total antibody levels in paired sera.

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• Chapter 49 : Hepatitis E Virus

  Authors: David A. Anderson, Iswar L. Shrestha
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    The hepatitis E virus (HEV) genome encodes three proteins; polyprotein open reading frame 1 (PORF1) (replicative polyprotein), PORF3 (required for replication in vivo but dispensable in cell culture), and PORF2 (capsid protein). Serologic assays based on truncated PORF2 protein (aa 112 to 660) expressed using the baculovirus system have yielded seroprevalence rates of over 20% in blood donors from Baltimore, MD, whereas rates of less than 2% were found in Australian blood donors using the open reading frame 2.1 (ORF2.1) protein (aa 394 to 660) expressed in Escherichia coli, yet the two assays appear to be equally sensitive when applied to samples from countries where HEV is endemic. The role of immunoglobulin A (IgA) in immunity to HEV infection is unknown, but as passive immunization with IgG appears to be sufficient for protection, it is likely that IgA is not essential. While hormonal factors may contribute to pathogenesis during pregnancy, other factors may also be important, such as the underlying general health status or chronic infection with HBV or hepatitis C virus in patients at the time of HEV infection. Conversely, in countries where HEV is endemic, it is often the most common cause of acute hepatitis. A variety of nucleic acid and serologic assays are used in research laboratories, but routine (commercial) diagnostic assays vary widely in their sensitivities and specificities. No specific symptomatic or anti-inflammatory treatments can be advised for hepatitis E.

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• Chapter 50 : Astrovirus

  Authors: Ernesto Méndez, Carlos F. Arias
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    Astroviruses have been found in several species of mammals and birds, a distinguishing feature used to classify them into two genera: Mamastrovirus and Avastrovirus. Human astroviruses (HAstV) were originally isolated in primary human embryonic kidney cells and subsequently adapted to grow in a continuous monkey kidney epithelial cell line (LLCMK2), although these cells could not be infected directly with astrovirus extracted from fecal specimens. Baby hamster kidney (BHK) cells, and probably others, support efficient replication when transfected with authentic astrovirus RNA or with in vitro-transcribed full-length astrovirus RNA, although they are not easily infected, suggesting that barriers at the entry level could determine the susceptibility of some cells to virus infection. In most temperate regions HAstV infections are more frequent in the winter, while in tropical regions astroviruses are more frequently detected during the rainy season. Contaminated food or water is the most frequent source of astrovirus infections. In turkey astrovirus infections, virus can be recovered from different organs, although the small intestine seems to be the only organ where astrovirus replicates. The mucosal immune system could be important in protecting individuals from repeated astrovirus infections. The severity of an astrovirus infection can be associated with the immune status of the patient, since immunodeficient patients have shown persistent infections with an extended course of infection and viral shedding. Prophylactic measures to avoid astrovirus spread in the population are important but may be difficult to achieve. Standard water chlorination, although not totally effective, can help to diminish astrovirus viability.

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• Chapter 51 : Coronaviruses

  Authors: Kenneth McIntosh, J. S. M. Peiris
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    Coronaviruses have been classified as members of the order Nidovirales, positive-sense RNA viruses that replicate using a nested ("nido") set of mRNAs. On the basis of antigenic relationships and genetic homologies, the coronaviruses were divided into three groups. The first contains human coronaviruses (HCoVs) 229E and several animal strains; the second contains OC43, murine hepatitis viruses (MHV) and several other animal strains; and the third contains infectious bronchitis virus (IBV) and several other avian coronaviruses. Coronaviruses, along with rhinoviruses, influenza virus, and respiratory syncytial virus (RSV), are commonly associated with acute respiratory disease in the elderly. Most of the human respiratory coronaviruses that were isolated in the 1960s were originally recovered during upper respiratory illness. A study of acute lower tract viral infections in patients after lung transplantation found respiratory viruses in 66%, with coronaviruses (OC43, 229E, and NL63) being present in rank order right behind rhinoviruses and ahead of others, and a highly significant association of viral infection with a decline in one-second forced expiratory volume (FEV-1), acute rejection, and likely development of bronchiolitis obliterans syndrome. The major complications of respiratory coronavirus infections have been seen in children or adults with underlying cardiopulmonary disease. Respiratory coronaviruses are difficult to grow in tissue culture. Coronaviruses can be detected by immunofluorescence of cells shed from the respiratory tract using commercially available reagents or polyclonal or monoclonal reagents developed in individual laboratories. Interest in prevention of severe acute respiratory syndrome (SARS) was intense from the very beginning of the epidemic.

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• Chapter 52 : Arthropod-Borne Flaviviruses

  Authors: Lyle R. Petersen, Alan D. T. Barrett
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    Flaviviruses have evolved principally by mutational change. Human disease caused by flaviviruses is classified as either (i) central nervous system (CNS) infection, (ii) hemorrhagic fever, or (iii) fever-arthralgia with or without rash. St. Louis encephalitis (SLE) virus is a member of the Japanese encephalitis (JE) antigenic complex, and antigenic cross-reactivities between SLE virus and other members of the complex are demonstrable with polyclonal and monoclonal antibodies. JE virus is the prototype of an antigenic complex that includes SLE and Murray Valley encephalitis (MVE) viruses, West Nile virus (WNV), and several other flaviviruses of lesser medical importance. The host range of MVE virus and susceptibility of cell cultures are provided in this chapter. Antigenic analyses differentiate strains of WNV from Africa, Europe, and the Middle East from strains isolated in India and the Far East. WNV is one of the most widely distributed of all arboviruses. Dengue virus fever is caused by four antigenically and genetically related but distinct viruses (dengue virus types 1 to 4) are distinguished by neutralization tests. Dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) is described in detail. The chapter also talks about the techniques for virus isolation and reverse transcriptase PCR (RT-PCR) from blood of acutely ill patients, and discusses the control of Aedes aegypti for dengue virus.

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• Chapter 53 : Hepatitis C Virus

  Authors: Yaron Rotman, T. Jake Liang
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    Hepatitis C virus (HCV), a member of the genus Hepacivirus in the Flaviviridae family, is a single-stranded RNA virus that infects humans and other higher primates and has a selective tropism to the liver. Although the HCV particle itself is difficult to demonstrate, by inferring from the virions of other Flaviviridae, the putative particle is composed of a nucleocapsid composed of the core protein and viral RNA, surrounded by a phospholipid membrane in which the viral envelope proteins are embedded. The replication cycle of the HCV can be divided into stages: binding and entry into the cell; polyprotein translation and processing; RNA replication; and packaging, assembly, and release of the virion. The current recommendations for disinfecting reusable endoscopic equipment by mechanical washing with detergent and soaking in 2% glutaraldehyde were shown to be sufficient to eliminate contamination with HCV. Hepatitis C can be transmitted vertically from mother to child. Successful eradication of hepatitis C with antiviral treatment significantly reduces, but does not eliminate completely, the risk of chronic hepatitis C (CHC). Serologic assays for detecting HCV infection were rapidly developed and improved following the initial discovery of the virus because of the urgent need to screen blood donors and prevent transmission. In general, antiviral treatment is indicated for any adult patient with CHC who is viremic and has elevated aminotransferases or histologic evidence of progressive liver disease, i.e., fibrosis extending beyond the portal tracts.

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• Chapter 54 : Alphaviruses

  Authors: David W. Smith, John S. Mackenzie, Scott C. Weaver
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    The alphaviruses are principally mosquito-borne, positive-strand RNA viruses in the family Togaviridae that exhibit a broad range of pathogenicity in humans and animals. The replication complexes of alphaviruses are associated with cytoplasmic membranes, and the main determinant of membrane attachment seems to be nsP1, which is hydrophobically modified by palmitoylation of cysteine residues. In humans, an age-dependent susceptibility of infants and the elderly to central nervous system (CNS) infection has been observed epidemiologically, although its pathogenesis has not been elucidated. Immature mouse neurons infected with Sindbis Virus (SINV) or Semliki Forest Virus (SFV) die of caspase-dependent apoptosis, while mature neurons survive by producing factors inhibiting virus-induced apoptosis. Apoptosis is induced at the time of alphavirus fusion with the cell membrane, and virus replication is not required. Mayaro virus (MAYV) is the principal New World representative of alphaviruses within the SFV complex. The epidemiological pattern is explained by the forest cycle of viral transmission, probably between Hemagogus mosquitoes and wild vertebrates, including monkeys and marmosets, analogous to the sylvatic cycle of yellow fever. The majority of infections with the arthritogenic alphaviruses are benign but temporarily debilitating. Barmah Forest virus (BFV), named after the site in northern Victoria where it was first isolated from Culex annulirostris mosquitoes, is antigenically distinct from other alphaviruses, including River virus (RRV) and SINV, that are also found in Australia. Alphaviruses principally are maintained in zoonotic transmission cycles in natural habitats.

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• Chapter 55 : Rubella Virus

  Author: David W. Kimberlin
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    Rubella virus is the sole member of the Rubivirus genus of the Togaviridae family. The other genus in the family of Togaviridae is Alphavirus. In contrast to the alphaviruses, which replicate in arthropods and in vertebrates, rubella virus has no invertebrate hosts. As humans are the only known natural host for rubella virus, the virus must circulate continuously within populations of people between periods of epidemics. While direct cellular destruction by rubella virus accounts for some of the tissue damage seen in congenital rubella syndrome, vascular injury and resulting insufficiency are more important in the pathogenesis of congenital defects. The consequences of in utero rubella virus infection can be considered broadly as belonging to one of three categories: (i) signs and symptoms that are transiently apparent in affected infants, (ii) permanent manifestations that are noted within the first year of life, and (iii) manifestations of congenital rubella that are delayed in onset until later in life (2 years of age to adulthood). Rubella virus infection is definitively diagnosed by isolation of rubella virus in tissue culture, using one of several cell lines and primary cell strains. Viral interference in African green monkey kidney (AGMK) cells is one common culture technique by which the presence of rubella virus is demonstrated.

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PART C SUBVIRAL AGENTS

• Chapter 56 : Hepatitis D Virus

  Authors: Antonia Smedile, Alessia Ciancio, Mario Rizzetto
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    Hepatitis delta virus (HDV) is the only member of the family Deltaviridae, genus Deltavirus. To establish infection in vivo, HDV depends on helper functions provided by hepatitis B virus (HBV). HDV encodes a single protein, the HDAg, which is translated from a 0.8-kb mRNA transcribed from the genomic RNA. The host range of HDV infection includes humans, chimpanzees, woodchucks, and ducks carrying HBV-related hepadnaviruses. A common feature of experimental HDV infection is the inhibition of HBV, shown by a decrease in the levels of HBsAg and HBV DNA in the serum and liver. The liver histologic pattern of hepatitis D is nonspecific and is similar to other types of viral hepatitis. The intralobular inflammatory cells were mainly macrophages containing periodic acid-Schiff-positive nonglycogenic granules. The main strategies for the prevention of HDV infection are (i) behavioral modifications to prevent disease transmission and (ii) active immunization against HBV. Changes in sexual practices in response to human immunodeficiency virus (HIV) infection have probably contributed to the declining incidence of HBV and HDV infection in the developed world and abroad, and improved methods for screening of blood products in blood banks have reduced the risk of transmission-associated hepatitis. HBV antisense oligonucleotides were constructed to alter HBV functions that are considered essential for HDV replication in vitro.

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• Chapter 57 : Transmissible Spongiform Encephalopathies

  Author: Adriano Aguzzi
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    Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are inevitably fatal neurodegenerative conditions which affect humans and a wide variety of animals. The most common form of prion disease in humans is sporadic Creutzfeldt-Jakob disease (sCJD). Human studies also point to a possible role for members of the classical complement cascade in prion pathogenesis; however, their precise role in prion disease is unknown. The majority of cases were caused by implantation of dura mater and injection of pituitary growth hormone. There is uncertainty surrounding the danger of transmission to humans represented by chronic wasting disease. In fact, even transmissibility of bovine spongiform encephalopathy (BSE) to humans relies on circumstantial evidence. Recent advances in neuroimaging, and especially in magnetic resonance imaging (MRI), have revealed that different human prion diseases have specific patterns. Tissue should be fixed in formalin for histologic assessment and snap-frozen for Western blotting. Western blotting of digested PrPSc reveals three distinct bands, corresponding to di-, mono-, and unglycosylated forms. Depending on the exact conditions under which the protease digestion and the Western blotting procedure are performed, between three and six different PrPSc types can be distinguished. The fact that the PrPSc types found in variant CJD (vCJD) patients and in BSE-diseased cattle are identical is one of the main arguments supporting the theory that BSE prions are responsible for the vCJD epidemic in humans.

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