Clinical Virology, Fourth Edition

• Chapter 2 : Respiratory Infections

  Author: John J. Treanor
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    Respiratory viral infections have a major impact on health. Acute respiratory illnesses, largely caused by viruses, are the most common illness experienced by otherwise healthy adults and children. Data from the United States, collected in the 1992 National Health Interview Survey, suggest that such illnesses are experienced at a rate of 85.6 illnesses per 100 persons per year and account for 54% of all acute conditions exclusive of injuries (1). A total of 44% of these illnesses require medical attention and result in 287 days of restricted activity, 94.4 days lost from work, and 182 days lost from school per 100 persons per year. The morbidity of acute respiratory disease in the family setting is significant. The Tecumseh study, a family-based surveillance study of respiratory illness, estimated that approximately one-quarter of respiratory illnesses result in consultation with a physician (2). Illness rates for all acute respiratory conditions are highest in young children, and children below the age of 9 have been estimated to experience between five and nine respiratory illnesses per year (3).

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• Chapter 3 : Viral Infections of the Central Nervous System

  Authors: Kevin A. Cassady, Richard J. Whitley
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    Central nervous system (CNS) symptoms (headache, lethargy, impaired psychomotor performance) are frequent components of viral infections; however, viral infections of the CNS occur infrequently and most often result in relatively benign, self-limited disease. Nevertheless, these infections have tremendous importance because of their potential for causing neurologic damage and death. The CNS is exquisitely sensitive to metabolic derangements and tissue injury. Clinical recovery is slow and often incomplete (1, 2). Patient history, while frequently suggestive of a diagnosis, remains an unreliable method for determining the specific etiology of CNS disease (1, 3). Tumors, infections, and autoimmune processes in the CNS often produce similar signs and symptoms (3). Different diseases may share common pathogenic mechanisms and therefore result in a similar clinical presentation. Furthermore, understanding disease pathogenesis provides a rational basis for the development of therapeutics including antivirals and strategies for the prevention of viral CNS infections.

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• Chapter 4 : Gastrointestinal Syndromes

  Authors: Eyal Leshem, Umesh D. Parashar
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    Gastroenteritis is a major cause of morbidity and mortality in humans, and viruses are important causes of this disease. While many viruses have been associated with diarrhea in humans, we know most about rotavirus because the methods used to detect it are best developed. Rotavirus remains the most important cause of severe diarrhea in children worldwide. Implementation of effective vaccines has resulted in a substantial reduction of the rotavirus disease burden. As rotavirus incidence drops in countries with mature vaccination programs, norovirus is increasingly being recognized as a major cause of pediatric diarrhea.

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• Chapter 5 : Viral Hepatitis

  Authors: Zina S. Valaydon, Stephen A. Locarnini, Alexander J.V. Thompson
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    Viral hepatitis describes a characteristic clinical syndrome resulting from necro-inflammatory pathology of the liver that is caused by one of the recognized hepatitis viruses. There are five established human hepatotropic hepatitis viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Acute hepatitis can also be a manifestation of other systemic viral infections, including herpesviruses (Epstein-Barr virus, cytomegalovirus, and herpes simplex virus) and yellow fever. Although the human hepatitis viruses can all cause the syndrome of acute hepatitis, they have distinct virology, phylogeny, routes of transmission, and risk of chronicity. In this chapter, we discuss the typical clinical syndromes and pathological features of viral hepatitis due to the hepatitis viruses A-E (Table 1), as well as the diagnostic evaluation of patients presenting with suspected viral hepatitis.

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• Chapter 6 : Viral Infections in Organ Transplant Recipients

  Author: John A. Zaia
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    Solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT) represent continually expanding fields of medicine, and, with many innovative methods for allograft management, new and unusual presentations of virus infections continue to occur. These new drugs or modalities aim to protect the SOT recipient from rejection of the newly acquired organ by the endogenous immune system or to protect the recipient from attack by the graft (Graft vs. Host Disease, GVHD). For example, in the mid-1960s, with the introduction of cytotoxic drugs such as azathioprine and cyclophosphamide in renal transplantation, pneumonitis associated with human cytomegalovirus (CMV) infection was first observed (1). Soon thereafter, it was noted that transplant recipients with Epstein-Barr virus (EBV) infection developed a previously unrecognized clinical syndrome, posttransplantation lymphoproliferative syndrome (PTLD) (2). In populations with a high prevalence of human herpesvirus 8 (HHV-8) infection, Kaposi sarcoma became a problem following SOT (3). With time, most of the endogenous herpesviruses and polyomaviruses of humans have emerged as particular problems. At the same time, respiratory viruses and hepatitis viruses complicate successful management of the SOT and HCT recipient as methods of iatrogenic immunosuppression change. The donor tissue itself can be the source of transmission of virus infection, including rabies (4), West Nile virus (5), human T leukemia virus type I (6), human immunodeficiency virus (7), lymphocytic choriomeningitis virus (8), and B19 parvovirus (9).

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• Chapter 7 : Viral Heart Disease

  Authors: Bruce M. McManus, Michael Seidman, Karin Klingel, Honglin Luo
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    Viral pathogens are well known to cause injury, inflammation, tissue destruction, and remodeling of heart muscle. Indeed, viruses are among the most common inciting agents to cause a condition termed acute myocarditis. This condition may also be provoked by bacteria, other pathogens, as well as toxins and autoimmune diseases, each of which could mimic the appearance of viral myocarditis. The reason for this phenotypic mimicry is that myocarditis is a process characterized pathologically by an inflammatory infiltrate of the myocardium with death or degeneration of adjacent myocytes, not typical of the ischemic damage associated with atherosclerotic coronary artery disease. The inflammation and damage may involve myocytes, interstitium, vascular elements, and pericardium. The inflammatory process affects cardiac function adversely, causing either ventricular dysfunction, arrhythmias, or both. The acute process may persist and manifest as chronic low-grade tissue inflammation and fibrosis associated with cardiomyopathy and frank heart failure.

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• Chapter 8 : Viral Diseases of the Skin

  Authors: Zeena Y. Nawas, Stephen K. Tyring
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    Viral infections cause a variety of cutaneous and mucosal manifestations that are either the result of primary viral replication within the epidermis or a secondary effect of viral replication elsewhere in the body. Three groups of viruses represent most primary epidermal viral replications: human papillomaviruses (HPV), herpesviruses, and poxviruses. Multiple virus families, including retroviruses, paramyxoviruses, togaviruses, parvoviruses, and picornaviruses, produce skin lesions secondarily. Other viruses, such as orthomyxoviruses and reoviruses, rarely induce skin lesions. Recognition of characteristic mucocutaneous manifestations of a variety of viral diseases is crucial. It either directly helps determine the etiologic agent or assists the clinician in deciding which additional diagnostic tests to order. Proper management of the patient can be initiated from the results of such tests.

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• Chapter 9 : Viral Hemorrhagic Fevers

  Authors: Gail Carson, Mike Bray, Cathy Roth
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    The term viral hemorrhagic fever (VHF) designates a syndrome resulting from infection with any of at least 30 different RNA viruses from four different taxonomic families (Table 1). Although they differ in certain features, all types of VHF are characterized by fever and malaise, a fall in blood pressure that can lead to shock, the development of coagulation defects that can result in bleeding, and for many VHF agents, high mortality. With the exception of dengue virus, which is maintained among human populations by mosquito transmission, all of the VHF agents persist in nature through cycles of infection in animals. In the past, therefore, the geographic range of each disease reflected that of the reservoir species. Human illness is an accidental event resulting from contact with an infected animal or its excretions or the bite of an infected arthropod. Subsequent human-to-human transmission through contact with infectious blood or secretions occurs with multiple haemorrhagic fever (HF) viruses and can cause devastating nosocomial outbreaks. Pathogenesis in humans, in most instances, only indirectly reflects the mechanisms by which the causative agent replicates in its reservoir host, but high levels of viremia are typical. Treatment is supportive for most VHFs, but progress is being made gradually in developing specific therapeutics. Vaccines are widely available for yellow fever, and recent studies indicate that effective dengue and Ebola virus vaccines are possible.

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• Chapter 10 : Viral Disease of the Eye

  Author: Howard M. Newman
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    The eye is a fascinating organ not only because of its complex anatomy but also because it is a partly immunologically privileged site, which protects itself from potentially destructive systemic immune responses. This characteristic, however, may hinder defense against infectious agents, including numerous viruses, which may manifest with a variety of ocular diseases (Table 1). The first part of this chapter discusses ocular anatomy and physiology, as well as the principle clinical syndromes, which are usually classified according to the affected anatomic structures. The latter part discusses the major viral ocular pathogens and highlights selected risk groups, such as infants and patients infected with human immunodeficiency virus (HIV).

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• Chapter 11 : Antiretroviral Agents

  Authors: Christine J. Kubin, 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. Almost 30 years later, more than 26 additional agents in six drug classes have been approved. These include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (entry inhibitor), a chemokine coreceptor antagonist (entry inhibitor), integrase strand transfer inhibitors (Table 1), and pharmacokinetic enhancers. This success is the result of a prodigious effort to dissect the virus’ replication cycle and the virion's interaction with its CD4 target cells to identify promising drug targets. It also illustrates the interdependency of the drug development process, knowledge of disease pathogenesis, and use of sensitive therapeutic monitoring tools like plasma HIV-1 RNA levels and drug resistance testing.

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• Chapter 12 : Antiherpesvirus Agents

  Authors: Claire L. Gordon, Christine J. Kubin, Scott M. Hammer
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    The first effective agents against herpesviruses were nucleoside analogs, such as idoxuridine, vidarabine, and trifluridine. Their use was eventually supplanted by the highly successful drug, acyclovir, which had significantly less toxicity. In early studies, intravenous acyclovir was shown to be superior to vidarabine for treating herpes simplex virus (HSV) encephalitis in healthy hosts and varicella zoster virus (VZV) infections in immunosuppressed subjects and to be equivalent to vidarabine in treating neonatal HSV infections.

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• Chapter 13 : Anti–Hepatitis Virus Agents

  Authors: Matthew L. Scherer, Chelsea Sammons, Brian Nelson, Scott M. Hammer, Elizabeth Verna
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    Antiviral therapy for hepatitis viruses, in particular hepatitis C virus (HCV), has evolved dramatically over the past 5 to 10 years. This chapter reviews agents that have been, or are being, developed to treat hepatitis B virus (HBV) (Chapter 32) and HCV (Chapter 54) infections. Detailed information is provided for approved agents and those in advanced stages of clinical development. Agents in earlier stages of development are described more briefly. Agents approved but rarely if ever used for a specific pathogen have been removed from this edition (e.g., interferon-α and HBV). The reader is referred to the respective disease-specific chapters for full discussions of the viral agents and the diseases they cause.

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• Chapter 14 : Antirespiratory Virus Agents

  Authors: Marcus R. Pereira, Benjamin A. Miko, Monica Mehta, Scott M. Hammer
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    This chapter reviews antiviral agents that have been, or are being, developed to treat or prevent respiratory viral 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 that are still in preclinical development are described briefly. The reader is referred to the respective pathogen-specific chapters for full discussions of the viral agents and the diseases they cause.

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• Chapter 15 : Diagnosis of Viral Infections

  Authors: Guy Boivin, Tony Mazzulli, Martin Petric
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    The clinical virology laboratory is an important and leading component of general microbiology that provides significant benefits to patient care. The traditional epidemiologic 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. This development is the result of many advances in diagnostic virology including improvement in cell culture (shell vial assays, mixed cell cultures, genetically engineered cell lines), availability of specific reagents such as monoclonal antibodies and, most importantly, the introduction of molecular techniques mostly based on polymerase chain reaction (PCR), which allow the sensitive and rapid detection of slowly growing or uncultivable viruses. The impact of the latter procedure is illustrated by the recent identification of several respiratory viruses including the human metapneumovirus (1), multiple coronaviruses including severe acute respiratory syndrome (SARS) (2) and Middle East respiratory syndrome (MERS) (3), human bocavirus (4), etc.

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• Chapter 16 : Immune Responses to Viral Infection

  Authors: Hendrik Streeck, Todd J. Suscovich, Galit Alter
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    The concept of “immunity” dates back to ancient Greece, where as early as the fifth century BC, documented cases of “immune” individuals were described who were related to individuals who recovered from the plague (1). However, it was not until the 10th century that specific “interventions” were described that could induce immunity. In both China and the Middle East, a process known as “variolation,” consisting of purposefully exposing healthy individuals to the contents of dried variola lesions, was actively practiced to prevent severe infection with smallpox. In the early 18th century, the practice of variolation was brought to Great Britain, where the development of the first vaccine by Jenner catalyzed the creation of the field of immunology. Beginning in the late 19th century, major breakthroughs, including the establishment of the “germ theory” by Koch and Pasteur, which held that disease was caused by bacteria or pathogens; the discovery of phagocytic cells by Metchnikoff; the identification of immune proteins in serum by von Behring and Kitasato; the identification of B cells and their regulation by Ehrlich; the discovery of lymphocytes by Gowan; the identification of pattern recognition receptors and innate immune activity by Janeway; and the discovery of dendritic cells, which link the innate and adaptive immune system, by Steinman, collectively gave rise to modern immunology and our current appreciation for the host immune response. This response has evolved to contain, eliminate, and remember virtually any pathogen to which it is exposed. This chapter reviews the components of the immune system, focusing on the innate and adaptive immune response to viral infection and how these arms of the immune system collaborate to prevent and control viral disease.

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• Chapter 17 : Immunization Against Viral Diseases

  Authors: Julie E. Ledgerwood, Barney S. Graham
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    Vaccines against viral infections are perhaps the greatest of all biomedical achievements for preventing disease and improving the public health. The most notable example is the success of smallpox vaccination. The practice of variolization (mechanical attenuation and intentional low-dose infection) to reduce the virulence of subsequent smallpox infection was started more than 1,000 years ago in India and China. However, smallpox vaccination was first performed by Jenner in 1796. This event marked the beginning of modern vaccine development and the first clinical test of vaccine efficacy. An expansive, sustained world health effort with global cooperation and leadership in combination with creative approaches, like the ring vaccination campaign, resulted in the 1980 WHO declaration that naturally occurring smallpox had been eradicated. Numerous other vaccines have had a significant impact on the severity and frequency of viral diseases, and many previously common viral illnesses are rarely encountered in modern clinical care (Table 1). In particular, vaccines against hepatitis A and B, poliovirus, measles, mumps, varicella, and rubella have markedly reduced the frequency of these infections in developed countries. Unfortunately, many of these infections remain major health problems, particularly in communities who choose to opt out of standard childhood immunizations (1) and in the developing world. A description of viral vaccines available for use in the United States is shown in Table 2.

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• Chapter 18 : Chronic Fatigue and Postinfective Fatigue Syndromes

  Author: Andrew R. Lloyd
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    Chronic fatigue syndrome (CFS) is the label most commonly applied to a symptom complex characterized by unexplained, persistent, and disabling fatigue, when no clear implication of an infective or other cause for the prolonged illness can be inferred (1). Constitutional symptoms, including myalgia, arthralgia, sore throat, headache, and tender lymph nodes, are also common. In addition, complaints of unrefreshing sleep, irritability, and neurocognitive abnormalities, like short-term memory impairment and concentration difficulty, are typical (1). CFS is also commonly termed myalgic encephalomyelitis, particularly in the United Kingdom, based on a premise of inflammation within the central nervous system—although this remains unproven (2). The US Institute of Medicine recently proposed that the condition be renamed “systemic exertion intolerance disease” to reflect a phenomenon characteristic of the illness, which is an exacerbation of fatigue and other symptoms after exercise or activity, termed “postexertional malaise” (3). However, only the name CFS has been accepted in common use internationally.

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DNA Viruses

• Chapter 19 : Poxviruses

  Authors: Stuart N. Isaacs, R. Mark Buller
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    Smallpox has long been known as a severe human disease (1, 2) and was already endemic in India 2,000 years ago before spreading to China and Japan in the east and Europe and North Africa in the West by about 700 A.D. It was introduced to the Caribbean with the African slave trade in 1518 and thence to Mexico in 1520, taking a terrible toll on the totally nonimmune Amerindians. Repeated introductions from Europe and, to a lesser extent, from Africa, into North America occurred from 1617 onward. With the discovery of vaccination by Jenner in the latter part of the 18th century (3), the disease was brought under control first by local initiatives, which became national, and finally global. Following the last identified case in 1977, the world was certified free of smallpox by the World Health Assembly in May 1980 (2). The subsequent drawdown of vaccine stockpiles and cessation of childhood vaccination programs have increased the vulnerability of the human population to a devastating smallpox epidemic and increased the threat of variola virus (VARV) as a bioweapon. This unintended consequence of the most successful vaccination program in history was exploited by the former Soviet Union, which weaponized VARV in contradiction to the 1972 Biological and Toxin Weapons Convention (4, 5). This occurrence raised concerns that other rogue nations or terrorist groups could also develop VARV or monkeypox virus (MPXV) as a bioweapon.

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• Chapter 20 : 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. Genital herpes was described in Sumerian literature (1). Greek scholars, particularly Hippocrates, used the word “herpes,” meaning to creep or crawl, to describe the spreading nature of skin lesions (2). Herodotus associated mouth ulcers and lip vesicles with fever and called it “herpes febrilis.” Many of these original observations likely emanated from Galen's deduction that the appearance of lesions was an attempt by the body to rid itself of evil humors, leading to the description “herpes excretins.”

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• Chapter 21 : Cercopithecine Herpesvirus 1 (B Virus)

  Author: Richard J. Whitley
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    B virus, endemic in macaque monkeys, has the unique distinction of being the only one of nearly 35 identified nonhuman primate herpesviruses that is highly pathogenic for humans. Infection has resulted in over 50 cases, with a mortality in excess of 80% in the absence of therapy. The actual number of cases worldwide is unknown. The unique biology of B virus includes its neurotrophism and neurovirulence. Because untreated B-virus infections are associated with high mortality in humans, individuals handling macaques or macaque cells and tissues are at risk for infection. Human infection is associated with a breach of skin or mucosa and subsequent virus infection. Fomites and contaminated particulates or surfaces can serve as a source of virus infection. Since the early 1980s, 80% of infected individuals given antiviral treatment have survived. Timely antiviral intervention is the only effective means of reducing B-virus-associated morbidity and preventing a fatal outcome.

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• Chapter 22 : Varicella-Zoster Virus

  Authors: Anne A. Gershon, Michael D. Gershon
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    Varicella-zoster virus (VZV) is the etiologic agent of two diseases, varicella (chickenpox) and zoster (shingles). Varicella, which occurs after the initial encounter with VZV, is a disease manifested by a pruritic rash accompanied by fever and other systemic signs and symptoms that are usually mild to moderate in nature. Most often, but not always, varicella is a self-limited infection of childhood. Live attenuated varicella vaccine was licensed for routine use in the United States in 1995 and after more than 20 years of use has changed the epidemiology of the disease, as the incidences of varicella and its complications have now significantly declined (1–3).

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• Chapter 23 : Cytomegalovirus

  Authors: Paul David Griffiths, Matthew Reeves
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    Human cytomegalovirus (HCMV) was first isolated in the mid-1950s, when the new technology of cell culture became available. It was isolated independently by three different investigators and named because of its cytopathic effect (CPE), which produced large, swollen, refractile cells causing “cytomegaly.” The virus is ubiquitous, having infected most individuals by early adulthood in developing countries and by late adulthood in developed countries. Most individuals show no symptoms as a result of primary infection, reactivation, or reinfection, indicating that the virus is well adapted to its normal host, which commits substantial immune resources to controlling HCMV. However, in individuals whose immune system is either immature (as in the fetus) or compromised by immunosuppressive therapy or human immunodeficiency virus (HIV) infection, HCMV can cause serious end-organ disease (EOD). Furthermore, accumulation of HCMV-specific T cells over decades contributes to immunosenescence. Thus, HCMV acts as an opportunist, damaging the very young and the very old as well as adults and children whose immune systems are impaired.

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• Chapter 24 : 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 (HBLV)’’ (1). It was found to mainly infect and replicate in lymphocytes of T-cell lineage (2). Subsequently, several reports described the isolation of similar viruses mainly from patients with HIV/AIDS. The characterization of HHV-6 indicated that the virus was antigenically and genetically distinct from the other five known human herpesviruses (1, 3). HHV-6 isolates are classified into two closely related groups that have been named variants A (HHV-6A) and B (HHV-6B). Primary HHV-6B infection occurs during infancy. This virus was recognized as the causative agent of exanthem subitum (ES) in 1988 (4).

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• Chapter 25 : Epstein-Barr Virus

  Author: Joyce Fingeroth
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    In the century preceding the discovery of Epstein-Barr virus (EBV), physicians speculated that a common clinical syndrome characterized by fever, tonsillar adenopathy, splenomegaly, and mononuclear leukocytosis termed glandular fever was caused by a pathogen (1). In 1920, the name infectious mononucleosis (IM) was introduced by Thomas P. Sprunt and Frank A. Evans to characterize this syndrome (2). Three years later, Hal Downey and C.A. McKinlay described the now-classic atypical lymphocyte as a common feature of this disease (3), and in 1932 John Rodman Paul and Walls Willard Bunnell demonstrated high titers of spontaneously occurring heterophile antibodies in the sera of patients with IM (4), ensuring more accurate diagnosis. In 1961, the British surgeon Denis P. Burkitt gave the first account outside of Africa of “The Commonest Children's Cancer in Tropical Africa” at Middlesex Hospital London, detailing the geographic relationship between Burkitt's lymphoma (BL) and conditions of temperature, altitude, and rainfall associated with development of Plasmodium falciparum malaria (5, 6). M. Anthony Epstein, who was in the audience, became intrigued by the idea that a biological agent might be involved in the etiology of BL, and in 1964, the Epstein laboratory analyzed BL biopsy samples by thin-section electron microscopy and discovered a new, large, icosahedral herpesvirus that could be directly reactivated from in vitro–grown BL cells (7). These initial findings were reported in The Lancet, and the virus was named after Epstein and his graduate student Yvonne Barr (8). Shortly thereafter, two independent groups (9, 10) demonstrated the ability of EBV to transform primary human B lymphocytes into permanently growing lymphoblastoid cell lines (LCLs), providing the first concrete evidence of the ability of EBV to promote human cancer. In 1968, Gertrude Henle and Werner Henle made two further critical observations: (1) that EBV seroconversion occurred during the course of acute IM (AIM) in a laboratory technician (9) and (2) that EBV-carrying LCLs spontaneously formed from a peripheral blood leukocyte culture obtained during the acute phase of the technician's illness. The Henles confirmed their observations through study of sera provided by James Corson Niederman and Robert W. McCollum, who collected blood from incoming Yale freshmen and later from individuals who developed AIM. This study and others demonstrated EBV-specific antibodies in the sera of the students who developed AIM, confirming the etiologic association between EBV and AIM (11).

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• Chapter 26 : Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV8)

  Authors: Yuan Chang, Shou-Jiang Gao, Patrick S. Moore
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    Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) causes several human cancers, including Kaposi's sarcoma (KS), primary effusion lymphomas (PEL), and some forms of multicentric Castleman's disease (MCD). KSHV is commonly associated with cancers among AIDS patients but it is also a significant public health problem in developing countries for both HIV-infected and uninfected populations. KSHV is a gammaherpesvirus with unique features in its gene products, gene distribution and evolution, and mechanisms of cellular transformation. The epidemiology of KS in different risk groups and geographic regions parallels the prevalence of KSHV infection. While modes of transmission of KSHV are still to be fully determined, specific measures can be implemented to prevent its spread. Specific assays, including serologic and antigen immunohistochemistry tests, have been developed that allow detection of infected patients and patient tissues. Understanding of the molecular mechanisms for KSHV-related pathogenesis should facilitate the detection, prevention, and therapy of KSHV and its associated cancers.

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• Chapter 27 : Adenoviruses

  Authors: Olli Ruuskanen, Jordan P. Metcalf, Matti Waris, Göran Akusjȁrvi
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    Adenoviruses were first isolated in 1953 from adenoids and tonsils surgically removed from children (1). Soon after the recovery of adenoviruses from patients with respiratory illness, their role as a major cause of febrile infections in young children and in army recruits was recognized. The illness was originally called acute respiratory disease (or ARD), but the signs and symptoms are similar to those of other viral respiratory syndromes, which should replace the old nonspecific expression.

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• Chapter 28 : Polyomaviruses

  Authors: John E. Greenlee, Hans H. Hirsch
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    Polyomavirus infections are widespread among humans and animals. The prototype of this viral family, polyoma virus of mice, was discovered in 1953 as an agent capable of producing tumors in its natural host (1). A second polyomavirus, murine K virus (KV; now known as mouse pneumotropic virus or MPtV), was discovered in 1952 (2). The simian polyomavirus, SV40, was discovered in 1960 as a contaminant of lots of rhesus monkey kidney cells used to prepare polio vaccine stocks (3). Infectious SV40, subsequently detected in both the Salk and Sabin polio vaccines, as well as in adenovirus vaccines, was inadvertently administered to millions of individuals worldwide (3).

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• Chapter 40 : Papillomavirus

  Author: William Bonnez
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    Human papillomaviruses (HPV) are a large group of viruses (more than 200 types identified) that infect the epithelium of the skin and mucous membranes. The infections can be latent, subclinical, or clinically manifest, causing lesions that range from the benign (warts, papillomas, condylomas) to the malignant. Some of these viruses are responsible for cutaneous warts; a different group of HPVs (types 6 and 11) is responsible for most genital warts. The major importance of HPVs is because 20 types (especially HPV-16 and -18) are regarded as the necessary, if not sufficient, cause of cervical cancer as well as other cancers of the vagina, vulva, penis, anus, and oropharynx. Although most sexually active individuals get infected with genital HPVs, most of these infections are transient and innocuous. It is the persistence of the high-risk oncogenic HPVs that leads to malignant transformation. Cancer caused by these viruses is preceded by a precancerous stage whose detection is the basis of cytologic screening (Pap smear) for cervical cancer. Ten years ago HPV vaccines were introduced for the prevention of diseases associated with HPV-16 and -18 and for the prevention of anogenital warts caused by HPV-6 and -11. The introduction of HPV vaccination has been a major advance because it is the first time a vaccine has been able to directly prevent virally induced cancers. When used broadly before the onset of sexual activity, HPV vaccination has caused a dramatic reduction in the incidence of genital warts and HPV-related cervical lesions. This should be the harbinger of a decline in the rates of cervical and other cancers.

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• Chapter 30 : Human Parvoviruses

  Authors: Maria Söderlund-Venermo, Kevin E. Brown, Dean D. Erdman
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    Parvoviruses have been isolated from a wide range of animals, including mammals, birds, insects, crustaceans, and reptiles. These viruses tend to be species-specific and can cause a variety of serious diseases in their host species (1). The first parvoviruses isolated from humans were adeno-associated parvoviruses, which have not yet been linked with disease. Until recently the only parvovirus associated with human disease was human parvovirus B19 (B19V), which was fortuitously identified in 1975 during an evaluation of tests for hepatitis B virus antigens (2). B19V has been associated with erythema infectiosum, transient aplastic crisis, chronic anemia in patients with impaired immune systems, hydrops fetalis, and purportedly a number of other conditions (3). Seven additional parvoviruses have recently been detected in humans by molecular screening for new sequences, including human bocavirus (HBoV)1–4, tetraparvovirus (PARV4), bufavirus (BuV), and tusavirus (TuV) (4–9). HBoV1 causes acute respiratory illness (10) and, as with HBoV2 and 3, possibly also encephalitis (11). The other recently discovered human parvoviruses are yet to be associated with human disease.

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• Chapter 31 : Anelloviridae

  Authors: Peter Simmonds, Colin P. Sharp
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    The family Anelloviridae includes the human torque teno virus (TTV) and related small nonenveloped viruses with circular single-stranded DNA genomes. Viruses of this family frequently or ubiquitously infect humans and a range of other mammalian species. Infections are characterized by their lifelong persistence and great genetic variability. Despite the original claimed association between anellovirus infection and hepatitis in humans when first discovered in 1997, no evidence convincingly links infections with anelloviruses to clinical disease.

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• Chapter 32 : Hepatitis B Virus

  Authors: Darren J. Wong, Stephen A. Locarnini, Alexander J.V. Thompson
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    It has been over 40 years since the discovery of the hepatitis B virus (HBV), and yet the disease it causes remains a major public health challenge. Worldwide, over 240 million people have chronic hepatitis B (CHB), with the majority being in the Asia-Pacific region, and there are almost 800,000 deaths each year as a direct consequence of infection (2). HBV infection is the ninth leading cause of death worldwide. The main public health strategy to control hepatitis B infection for the last 30 years has been primary prevention through vaccination. According to WHO, as of 2013, more than 180 countries have now adopted a national policy of immunizing all infants with hepatitis B vaccine. However, a strategy of secondary prevention is clearly necessary to reduce the risk of long-term complications (cirrhosis, liver failure, and hepatocellular carcinoma) in those individuals who have CHB. The risk of these complications is strongly associated with persistent high-level HBV replication (3–5). Antiviral agents active against HBV are available. The long-term suppression of HBV replication has been shown to prevent progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC) and liver-related deaths. However, currently available treatments fail to eradicate the virus in most of those treated, necessitating potentially lifelong treatment. WHO has set targets for both morbidity and mortality. A cure for CHB remains elusive, and a significant research effort is now being directed toward this goal.

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• Chapter 33 : Human Lymphotropic Viruses: HTLV-1 and HTLV-2

  Authors: Roberta L. Bruhn, Renaud Mahieux, Edward L. Murphy
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    Human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) and the more recently recognized HTLV-3 and HTLV-4 are human retroviruses of the genus Deltaretrovirus originally derived from closely related simian viruses. Proviral DNA is integrated in the host genome and propagated by lymphocytic division with only a minimal production of infectious virus. A small viral genome encodes several structural and regulatory proteins that in concert with the host cellular immune response control the burden of infection, as measured by the proportion of lymphocytes harboring HTLV proviral DNA. Most chronically infected humans are asymptomatic, but 2% to 4% of HTLV-1 carriers develop a mature T-cell malignancy called adult T-cell lymphoma (ATL). HTLV-2 infection does not cause malignant disease. Another 1% to 2% of HTLV-1 and HTLV-2 carriers develop a spinal cord disease known as HTLV- associated myelopathy (HAM) characterized by a progressive weakness and spasticity of the lower extremities as well as a hyperactive bladder. Various inflammatory conditions have been associated with infection, and long-term mortality may be increased. HTLV-1 and HTLV-2 are transmitted from mother to child via breast-feeding, by sexual intercourse, and parenterally by the infusion of infected blood or injection drug use. From its presumed origins in Central Africa and Melanesia, HTLV-1 has spread globally along with human migrations and the historical slave trade. HTLV-2, endemic in Amerindian and African pygmy populations, has had a more limited geographic distribution except for hyperendemic spread among injection drug users (IDUs) in the United States and Europe.

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• Chapter 34 : Human Immunodeficiency Virus

  Authors: John C. Guatelli, Robert F. Siliciano, Daniel R. Kuritzkes, Douglas D. Richman
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    Infection with human immunodeficiency virus type 1 (HIV-1) is prevalent throughout the world and is characterized by a progressive deterioration of the immune system that is usually fatal if untreated. As of 2013, HIV-1 was estimated to infect 35 million people worldwide (http://www.who.int/hiv/data/en/). Over 95% of these infections are in low- and middle-income countries among young adults. The acquired immunodeficiency syndrome (AIDS) that results from chronic HIV-1 infection is the sixth leading cause of mortality worldwide; it was estimated to have caused 1.5 million deaths in 2013 (http://www.who.int/hiv/data/en/).

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• Chapter 35 : Colorado Tick Fever and Other Arthropod Borne Reoviridae

  Authors: Steven Yukl, Joseph K. Wong
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    Among arthropod-borne viral infections, Colorado tick fever is second in incidence in North America only to West Nile fever (1). As with other viruses, evidence of infection by arthropod-borne reoviruses, including many newly identified viruses, as the cause of both human and veterinary disease continues to accumulate. This likely reflects advances in detection and diagnostic methods and perhaps also evolving demographic conditions that facilitate contact between human populations and the insect vectors that transmit these viral infections. The clinical importance of reoviruses will doubtless continue to change in the wake of the emergence of other arthropod borne infections such as Zika and dengue viruses.

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• Chapter 36 : Rotaviruses

  Authors: Manuel A. Franco, Juana Angel, Harry B. Greenberg
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    Acute infectious diarrhea is one of the two most frequent diseases of young children. Until the early 1970s, numerous unsuccessful attempts were made to grow viral agents responsible for acute infectious diarrhea of children. The etiologic agent of epizootic diarrhea of infant mice (EDIM) was identified by electron microscopy in 1963 (1). Nonetheless, it was only with the discovery of the virus responsible for calf scours (with this same approach) in 1969 by Mebus et al (2) and of the human Norwalk virus by Kapikian et al (3) in 1972 that the methodology for identification of the viruses responsible for severe diarrhea in children was established. Using electron microscopy, Bishop et al (4) identified the first human rotavirus in an intestinal biopsy from a child with diarrhea. At roughly the same time, other groups used immune electron microscopy to identify the enteric caliciviruses and astroviruses, viruses that were also difficult to grow in vitro, as additional causes of acute infectious diarrhea in children and adults. Shortly after the discovery of human rotaviruses, it was realized that the EDIM virus and the calf scours virus were morphologically and antigenically related, and all these strains were grouped in the genus rotavirus. In rapid order, rotaviruses were shown to be among the most important pathogens of acute diarrhea in the young of many animals, including humans.

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• Chapter 37 : 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, MPV), and the parainfluenza viruses (PIVs) are the most important causes of lower respiratory tract illnesses in infants and children. RSV was first isolated from chimpanzees with coryza in 1956 (1) but was soon shown to be the major cause of bronchiolitis and pneumonia in infants (2). RSV was named after the cell fusion that is characteristic of its growth in some continuous cultured cell lines. PIV types 1, 2, and 3 were first recovered in 1956 (3, 4) and were recognized as the major causes of croup, or laryngotracheobronchitis, in children. PIV types 4A and 4B have been recovered from adults and children with upper respiratory illnesses but historically were difficult to isolate in cell culture (5). MPV was first discovered in the Netherlands in 2001 (6) and soon thereafter was documented to be an important cause of lower respiratory tract illness in children worldwide. In older children and adults, these three viruses cause frequent reinfections that are generally mild in healthy persons, but they may cause serious disease in the very young or elderly, immunocompromised patients, and persons with underlying cardiopulmonary diseases.

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• Chapter 38 : Measles

  Authors: William J. Moss, Diane E. Griffin
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    Measles is a highly contagious disease caused by infection with measles virus (MeV), and it has caused millions of deaths since its spread within human populations thousands of years ago. Disease begins with fever, cough, coryza, and conjunctivitis followed by the appearance of a characteristic maculopapular rash. Genetically, MeV is most closely related to rinderpest virus, a pathogen of cattle that was recently eradicated. MeV was originally a zoonotic infection that adapted to humans 5,000 to 10,000 years ago when populations achieved sufficient size in Middle Eastern river valley civilizations to maintain a continuous chain of transmission among susceptible individuals. Subsequent introduction of MeV into naive populations resulted in high mortality. Millions died as a result of European exploration of the New World, largely due to the introduction of diseases such as smallpox and measles into native Amerindian populations (1).

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• Chapter 39 : Mumps Virus

  Authors: John W. Gnann Jr., Donald R. Latner
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    Mumps virus, a member of the paramyxovirus family, causes a distinctive and generally benign systemic infection that is clinically characterized by fever and parotitis. In older literature, mumps was often termed “epidemic parotitis.” Historically, mumps occurred commonly among school-aged children but dramatically declined following the introduction of routine vaccination. Significant mumps outbreaks continue to occur, however, among previously infected or vaccinated individuals for reasons that are not fully understood. These cases of reinfection or vaccine failure can sometimes be difficult to diagnose due to mild clinical presentations and can be difficult to confirm due to limitations of current laboratory testing.

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• Chapter 40 : Zoonotic Paramyxoviruses

  Authors: Danielle E. Anderson, Lin-Fa Wang
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    This chapter focuses on emergent paramyxoviruses that are associated with zoonotic disease. Hendra virus (HeV), Nipah virus (NiV), Menangle virus (MenPV), and Sosuga virus (SosPV) are known to have caused severe zoonotic infections, and Tioman virus (TioPV), Achimota virus (AchPV), and Mojiang virus (MojPV) are also suspected of causing them. These viruses, which have emerged or been detected over the last two decades, are potential threats to both livestock animals and humans (Table 1). In particular, HeV and NiV have caused fatal diseases in animals and humans, and outbreaks of NiV continue to occur almost annually. Molecular biological studies have made substantial contributions to the characterization of emergent zoonotic paramyxoviruses. Sequencing studies provide an accurate picture of the relative taxonomic position of these viruses and provide rapid diagnostic capabilities. In the case of outbreaks of NiV in Malaysia, Bangladesh, and India, molecular biological data quickly identified the etiologic agent present, and reverse transcriptase PCR (RT-PCR) and serologic assays were used to rapidly confirm NiV infections in humans and animals (1–4).

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• Chapter 41 : Rhabdoviruses

  Author: Alan C. Jackson
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    Rabies is an acute encephalomyelitis of humans and animals caused by infection with rabies virus. Rabies virus is usually transmitted by an animal bite. Worldwide, dogs are the most important rabies vector, whereas in North America wild animals, especially bats, are the main threat to humans. After a delay at the site of entry, rabies virus spreads through the nervous system within axons by fast axonal transport. Rabies can be very effectively prevented after a recognized animal exposure with wound cleansing and administration of rabies vaccine and rabies immune globulin. Rabies typically develops after an incubation period of 20 to 90 days following the exposure. There are both encephalitic and paralytic forms of rabies and the disease is virtually always fatal after clinical onset. Hydrophobia is a characteristic clinical feature of encephalitic rabies. Progressive weakness involving the limbs and face occurs in paralytic rabies, which often begins close to the site of the wound. Pathological changes in rabies include the presence of eosinophilic inclusions called Negri bodies in the cytoplasm of neurons and inflammatory changes. Imaging studies may be normal and do not show specific abnormalities. A laboratory diagnosis can be made antemortem with the detection of rabies virus antigen or RNA in tissues (e.g., skin) and/or body fluids (e.g., saliva) and with serological testing. There have been rare survivors of rabies, but there is no known effective therapy.

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• Chapter 42 : Filoviruses

  Authors: Mike Bray, Daniel S. Chertow
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    The filoviruses are nonsegmented, negative-sense RNA viruses in the family Filoviridae, order Mononegavirales. The genus Marburgvirus consists of a single species of related viruses, for which bats in Central Africa have recently been found to be a reservoir. The other genus, Ebolavirus, contains four species (Zaire, Sudan, Bundibugyo, and Ivory Coast) indigenous to Africa, and a fifth, Reston virus, found in the Philippines. It is likely that the African Ebola species are also maintained in bats, but attempts to recover infectious virus from captured animals have been unsuccessful. Except for the Reston agent, all filoviruses cause severe disease in humans, with fatality rates in outbreaks often exceeding 50%.

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• Chapter 43 : Influenza Virus

  Authors: Frederick G. Hayden, Peter Palese
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    Influenza viruses are unique among the respiratory viruses with regard to their frequent antigenic changes, seasonality, and impact on the general population. They can cause explosive outbreaks of febrile respiratory illness across all age groups and often substantial mortality, particularly in aged and chronically ill persons. Epidemics resembling influenza have been recorded since antiquity. The plague of Athens in 430 to 427 BC, described by Thucydides, has been postulated to have been due to epidemic influenza complicated by toxigenic staphylococcal disease (1). The greatest effects of influenza are seen when novel strains, to which most persons are susceptible, cause worldwide outbreaks, or pandemics. The most profound of these in modern times was the 1918 pandemic that may have claimed as many as 100 million lives worldwide (2). Sequencing of RNA fragments from tissue samples taken from 1918 pandemic victims enabled reconstruction of the extinct 1918 virus and study of its virulence in animal models (3, 4).

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• Chapter 44 : Bunyaviridae: Orthobunyaviruses, Phleboviruses Nairoviruses, and Hantaviruses

  Authors: Gregory J. Mertz, Clas Ahlm, Colleen B. Jonsson
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    The family Bunyaviridae is the largest family of viruses and includes many known human, animal, and plant 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 hantavirus cardiopulmonary syndrome (HCPS), which is also referred to in the literature as hantavirus pulmonary syndrome (HPS). Sandfly fever, RVF, and HFRS are common. Although most of the remaining diseases probably cause no more than a few hundred cases each year, some are associated with a high mortality rate (particularly CCHF and HCPS), and two (CE and HCPS) are endemic in North America.

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• Chapter 45 : Arenaviruses

  Author: Daniel G. Bausch
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    Viruses of the Arenaviridae family (genus Arenavirus) are zoonotic; they are maintained in nature, with a few possible exceptions, by chronic infection in rodents of the superfamily Muroidea (1). Over 40 arenaviruses have been identified, although less than half of these are clearly recognized as human pathogens (Table 1 and Figures 1 and 2). Arenaviruses continue to be discovered at a quickening pace in recent decades (2–10).

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• Chapter 46 : Enteroviruses

  Author: José R. Romero
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    The genus Enterovirus (EV) was so designated because its members replicate primarily in the human gastrointestinal (GI) tract. The original taxonomic classification of the EVs recognized 64 prototype serotypes within the family Picornaviridae (“pico” meaning small, “rna” for ribonucleic acid genome) (Table 1) (1, 2). Additional serotypes continue to be discovered, and the original genus currently has more than 100 confirmed serotypes (3, 4). The “traditional” species designation within the genus includes the polioviruses (PV), coxsackieviruses A and B (CV-A and CV-B, respectively), echoviruses (E), and the “numbered” EVs (Table 1). The original speciation of the EVs was based on the ability of individual serotypes to grow in various cell cultures and produce disease in animal systems (1).

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• Chapter 47 : Rhinovirus

  Authors: Wai-Ming Lee, James E. Gern
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    Rhinoviruses (RVs), members of the Picornaviridae family (1), constitute the largest group of respiratory viruses. RVs are recognized as causing more than 50% of all acute respiratory infections and represent the single most important causative agent of common colds. The name “rhinovirus” stems from the virus's special adaptation to infect the nasopharynx. It was already known in 1930 that “colds” were easily transmitted from human to human and to apes, and that the responsible agent was probably a virus (2, 3), but it was not until 1956 that the first RV was discovered by isolation in cell culture (4, 5). The discovery of the low temperature optimum (32–35°C) for viral replication (6), the development of sensitive primary human embryonic lung cell cultures (WI-38 and MRC-5), and the continuous H1-Hela cell line (7, 8) facilitated the isolation, classification, and epidemiological and biological studies of RVs. A total of 100 serotypes were identified over the next 30 years (9). The first complete genome sequence was determined for RV14 in 1984 (10), a reverse genetics system was developed in 1985 (11), and the X-ray crystallographic structures of the viral capsids of five serotypes (1A, 2, 3, 14, and 16) were solved soon afterward (12–17). The recent use of more sensitive RT-PCR-based molecular assays for RV identification has generated clear evidence that RV infections are also common causes of more severe lower respiratory illnesses, such as bronchiolitis, pneumonia, exacerbations of asthma, and other chronic lung diseases (18–22). RT-PCR has also led to the discovery of more than 50 genotypes of previously unrecognized RVs that belong to a new species (RV-C). These viruses escaped traditional culture-based detection (23–26). This discovery has promoted a new wave of interest in RV research.

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• Chapter 48 : Hepatitis A Virus

  Authors: Sara E. Williford, Stanley M. Lemon
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    Hepatitis A is an acute, self-limiting infection of the liver by hepatitis A virus (HAV), an enterically transmitted, hepatotropic member of the picornavirus family. Although HAV infection may occasionally result in fulminant hepatitis and death, it is not recognized to cause persistent infection or chronic hepatitis, even in severely immunocompromised individuals.

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• Chapter 49 : Human Caliciviruses

  Authors: Robert L. Atmar, Mary K. Estes
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    Norwalk virus (NV) was first recognized from an outbreak of epidemic gastroenteritis in an elementary school in Norwalk, Ohio in 1968, in which 50% of the students and teachers became ill and secondary cases occurred in 32% of family contacts (1). Subsequently, NV was visualized using immune electron microscopy (IEM) and described as a 27-nm filterable agent (2). This provided definitive proof that viruses cause diarrhea, an idea initially proposed during the 1940s and 1950s when a filterable infectious agent (although not propagated in cell culture) was passaged serially in volunteers. The first clear description of the basic virological, clinical, and immunological responses to nonbacterial infections came from studies in volunteers administered a bacteria-free fecal filtrate of NV (3). The history of these early investigations leading to visualization of the agent by IEM provides an excellent example of how major scientific advances often require and parallel new technological opportunities (4). The subsequent application of IEM to other diarrheal stool samples ultimately led to the discovery of other viral agents of gastroenteritis and hepatitis A virus (see Chapters 4, 25, 34, and 48). The later cloning and expression of the NV genome resulted in the development of new assays and reagents that permit large-scale epidemiologic studies.

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• Chapter 50 : Hepatitis E Virus

  Authors: Harry R. Dalton, Nassim Kamar, Jacques Izopet
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    Hepatitis E was recognized as a disease in 1980 following a large outbreak of unexplained hepatitis in Kashmir, India, in 1978. The outbreak affected 52,000 individuals, mostly young adults, with a self-limiting hepatitis similar to hepatitis A (1). However, this was not hepatitis A, because there was a very high mortality rate in afflicted pregnant women. Further, most of those infected had previously been exposed to HAV (2). In 1983, the causative virus was discovered by electron microscopy in the stool of a scientist from the former USSR who drank a pooled fecal extract from Soviet troops with unexplained hepatitis serving in Afghanistan (3). The viral genome was sequenced and given the name HEV in 1990 (4). Many of the historical outbreaks of unexplained hepatitis in Asia and other developing areas were subsequently found in retrospect to be caused by HEV (5, 6).

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• Chapter 51 : Astrovirus

  Authors: Carlos F. Arias, Tomás López
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    Astroviruses are present in a wide variety of animal species, including mammals and birds. In many species, including humans, these viruses are associated with gastrointestinal diseases and, more recently, with encephalitis and diverse neurological manifestations. Human astroviruses (HAstVs) were first identified in fecal samples of children with diarrhea by electron microscopy as small particles with a star-like morphology, the feature that Madeley and Cosgrove (1) used in 1975 to name this group of viruses (astron-star in Greek). This morphology, however, is observed in only a small proportion of the particles present in stool samples, and expertise in electron microscopy is required for their identification. Development of more sensitive and specific diagnostic methods, such as enzyme immunoassays (EIA) and reverse transcription, coupled with polymerase chain reaction (RT-PCR), in diverse formats have revealed that HAstVs represent serious gastrointestinal pathogens that affect distinct groups in the population. Adaptation of HAstVs to tissue culture and the molecular characterization of human, as well as of animal, viruses have contributed to recent advances in the understanding of their molecular biology; however, an animal model to study HAstV pathogenesis is still required.

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• Chapter 52 : Coronaviruses

  Author: J.S.M. Peiris
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    The name coronavirus derives from the Latin word “corona,” meaning crown or halo, and this refers to the “crown-like” fringe of projections seen on the surface of virus particles when viewed under the electron microscope (Fig. 1). The first coronavirus to be recovered was infectious bronchitis virus (IBV) from chickens with respiratory disease, reported by Beaudette and Hudson in 1937 (1). Murine hepatitis viruses (MHV) (2) and transmissible gastroenteritis virus (TGEV) in swine (3) were then recognized as causes of other animal diseases. The relationship between these viruses was not appreciated until after the human coronaviruses (HCoVs) were discovered in the 1960s and the Coronavirus genus was defined. Tyrrell and Bynoe (4) described the first HCoV, designated as B814, by inoculating specimens from a patient with a “cold” onto organ cultures of human embryonic trachea. Using electron microscopy (EM), the virus was found to resemble avian IBV (5). At about the same time, Hamre and Procknow (6) recovered five HCoV strains from medical students with colds and cultivated them in human embryo kidney cells. The prototype strain HCoV 229E had morphology that was identical to that of B814 and IBV. McIntosh et al. used the organ culture technique to recover six further strains, including the prototype strain HCoV OC43 and three other strains considered antigenically unrelated to either OC43 or 229E (7).

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• Chapter 53 : Arthropod-Borne Flaviviruses

  Authors: Lyle R. Petersen, Alan D.T. Barrett
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    In 1901 the prototype flavivirus disease, yellow fever, was the first human illness shown to be caused by a filterable virus, and, in 1927, it became the first member of the flavivirus family to be isolated. The Flaviviridae derive their name from yellow (flavus, Latin) fever. From the medical perspective, the flaviviruses are the most important group of arthropod-borne viruses (arboviruses). Dengue fever and dengue hemorrhagic fever (DHF) are major causes of human morbidity worldwide. Yellow fever remains an epidemic threat in Africa and South America. Since its introduction into North America, West Nile virus (WNV) has caused annual outbreaks of encephalitis and febrile illness in North America and has spread throughout the Americas as far south as Argentina; Japanese encephalitis (JE) remains a major cause of viral encephalitis in Asia.

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• Chapter 54 : Hepatitis C Virus

  Authors: Christopher Koh, Qisheng Li, Jake Liang
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    Hepatitis C virus (HCV), a member of the genus Hepacivirus in the Flaviviridae family (1), is a single-stranded RNA virus that infects humans and other higher primates, and has a selective tropism to the liver. Following exposure, HCV is able to evade the host's immune system and establish a chronic, often asymptomatic, infection that may lead to liver failure, hepatocellular carcinoma, and death. Transmitted primarily by exposure to infected blood, but also through sexual and perinatal routes, the virus is estimated to infect 2.8% of the world's population (2). Originally termed non-A, non-B hepatitis, infection with HCV was a frequent cause of transfusion-related hepatitis until discovery of the virus in 1989 (3, 4) and the subsequent development of effective screening methods. Many substantial advances have recently been made in treating HCV infection, and it is now possible to cure over 90% of patients with HCV infection. These advances also provide promising opportunities for future public health efforts to effectively reduce the disease burden of this global infection.

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• Chapter 55 : Alphaviruses

  Authors: David W. Smith, John S. Mackenzie, Ilya V. Frolov, 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 (1, 2). Members of the genus are distributed worldwide in diverse ecological niches, where they are usually maintained in cycles between mosquitoes and birds or mammals. While human infections generally are incidental to the transmission cycles, in some instances human-mosquito-human cycles can maintain transmission and lead to large outbreaks and epidemics. Among the 24 alphaviruses listed in Table 1, 16 have been associated with human illness. Clinically, these manifest most commonly as polyarthralgia, often accompanied by fever and/or rash, or as central nervous system (CNS) infections. In addition to the alphaviruses circulating between mosquitoes and vertebrate hosts, a single example of an alphavirus, restricted to mosquitoes, has recently been described, Eilat virus (EILV) (3), and there are two known aquatic species, southern elephant seal virus (SESV) and salmon pancreatic disease virus (SPDV), that are likely to have lice as vectors (4, 5). This chapter reviews general aspects of the virology, pathogenesis, laboratory diagnosis, and prevention of the alphavirus infections, followed by more detailed discussion of those that cause human disease.

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• Chapter 56 : Rubella Virus

  Author: David W. Kimberlin
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    Rubella is a benign disease when acquired by a child or adult, but causes significant sequelae to a developing fetus when intrauterine transmission occurs. Following the devastating worldwide pandemic in 1962–1965, a safe and effective rubella vaccine was developed and widely utilized. As a consequence, the occurrence of congenital rubella syndrome has decreased dramatically in those regions of the world with rubella vaccination programs. In 2015 the Americas region became the first World Health Organization (WHO) region in the world to be declared free of endemic transmission of rubella. Despite this, rubella continues to circulate in other parts of the world, including a large outbreak in Japan occurring since 2012, and approximately 100,000 cases of congenital rubella syndrome still occur worldwide. Given the ease and frequency of global travel, however, clinicians need to remain aware of rubella even in the United States, so that imported cases can be identified and managed accordingly. This chapter reviews the current knowledge of the natural history, pathogenesis, diagnosis, treatment, and prevention of rubella.

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• Chapter 57 : Infections Caused by Bornaviruses

  Authors: Ralf Dürrwald, Norbert Nowotny, Martin Beer, Jens H. Kuhn
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    Bornaviruses (Mononegavirales: Bornaviridae) form enveloped virions with nonsegmented, single-stranded negative-sense genomes (∼8.9 kilobases). They naturally infect mammals (e.g., bicolored white-toothed shrews [Crocidura leucodon], equids, sheep, variegated squirrels [Sciurus variegatoides] but rarely other mammals including humans) and a wide variety of birds and snakes. Bornaviruses have unique characteristics, such as 1) replication in the nucleus using cellular splicing machinery for generation of mRNAs and integrating bornaviral elements into the host-cell genome; 2) genome trimming for generation of RNAs that probably do not trigger innate immune responses in infected cells; and 3) suppression of apoptosis in infected cells mediated by the accessory protein (X), leading to persistent noncytolytic infection.

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• Chapter 58 : Hepatitis D

  Authors: Mario Rizzetto, Antonina Smedile, Alessia Ciancio
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    Hepatitis D virus (HDV) is unique in animal virology and pathology. It has a circular RNA genome of the smallest size among human viruses, requires the hepatitis B surface antigen (HBsAg) capsid provided by the hepatitis B virus (HBV) to assemble into infectious virions, parasitizes the transcriptional machinery of the host by hijacking cellular RNA polymerases to replicate its RNA genome, and is replicated by a rolling circle mechanism unknown in mammalian cells.

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• Chapter 59 : Prion Diseases

  Authors: Christina J. Sigurdson, Mee-Ohk Kim, Michael D. Geschwind
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    Prion diseases are infectious and fatal neurodegenerative disorders of humans and animals caused by the accumulation of a misfolded and aggregated form of the cellular prion protein (1, 2). The term “prion” was coined by Stanley Prusiner and is derived from the words “proteinaceous infectious particle” (2). Prions are misfolded forms of a normal protein called the “prion protein” and by definition are infectious. In most prion diseases, prions are abundant in the brain and spinal cord and can spread between patients iatrogenically, for example, through neurosurgical procedures or grafts of prion-contaminated dura mater (3). The classic neuropathologic lesion neuropatholog in the brain of a prion-infected patient is spongiform degeneration with neuronal loss, activated astrocytes and microglia, and a notable lack of peripheral inflammatory cells (4).

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