Human respiratory syncytial virus

Recent developments involving microbiology and related science policy matters as well as drug, vaccine, and diagnostic product approvals include:

• U.S. Food and Drug Administration (FDA) officials in June approved Xpert Carba-R Assay, an infection control aid that tests patient specimens to detect specific genetic markers associated with bacteria that are resistant to carbapenem antibiotics. The new diagnostic assay, which detects many but not all types of carbapenemase genes, is manufactured by Cepheid of Sunnyvale, Calif.

• FDA officials in June approved Epclusa, a fixed-dose combination tablet containing sofosbuvir, an antiviral drug approved in 2013, and velpatasvir, a new drug, for treating patients infected chronically with the hepatitis C virus (HCV). This first combination product for treating all six major forms of HCV is produced by Gilead Sciences, Inc., of Foster City, Calif.

• Members of the Advisory Committee on Immunization Practices (ACIP) in June recommended to officials at the Centers for Disease Control and Prevention (CDC) in Atlanta, Ga., that the live attenuated influenza vaccine, known commercially as FluMist, not be used during the 2016–2017 flu season. ACIP cited the vaccine's “relatively lower effectiveness” during the past several years as the main reason behind its recommendation. The FluMist Quadrivalent vaccine is produced by MedImmune, a subsidiary of AstraZeneca.

• A new business model is needed for developing antibiotics, one that does not depend on high revenues from selling large amounts of product, according to Kevin Outterson from Boston University School of Law in Boston, Mass., and his collaborators. Details appeared 14 June 2016 in PLoS Medicine (doi:10.1371/journal.pmed.1002043).

• Commercially available field tests for the rabies virus, specifically those based on lateral flow devices, have “serious problems,” say Conrad Freuling from the Friedrich-Loeffler-Institute in Greifswald, Germany, and his collaborators. Although highly specific, these tests have low sensitivity and tend to yield false-negative results, the researchers note. Details appeared June 23, 2016 in PLOS Neglected Tropical Diseases (doi:10.1371/journal.pntd.0004776).

Neonatal and infant mice, easily maintained in the laboratory, were found to be susceptible to certain viruses such as arboviruses and coxsackieviruses. Tissue culture systems were utilized to study a torrent of human viral isolates and their relationships to human disease. Public health virology laboratories served to introduce and refine techniques in diagnostic virology that would become essential to hospital laboratories charged with the care of individual patients at the time of their illness. Hsiung contributed to the advancement of diagnostic virology with numerous publications concerning the functions of the diagnostic lab and individual reports on viral isolates. She developed several animal models of human diseases, including transplacental transmission of cytomegalovirus (CMV) in the guinea pig as a model of congenital human CMV infection. Despite the number of enteric viral isolates in tissue culture, the isolation of the most significant viral causes of gastroenteritis would await further technological advances such as immunoelectron microscopy. While attention was focused on disease associations of viruses and clinical textbooks were organized by viral diseases of organ systems, the increasing amount of information about the biological and physical characteristics of viral isolates spurred taxonomic formulations. The next era following the explosion of viral isolations in tissue culture would make use of immunological, chemical, and electron microscopic techniques.

Viruses and their hosts have evolved to coexist by maintaining viral homeostasis. At the organism level, the immune system of the host plays a major role in clearing the infection or driving the viruses to enter a latent phase. In addition to the direct action of the cells of the immune system, various cytokines, most importantly the interferons (IFNs) system, produced by them are critically important in this process. The majority of the interferon-stimulated genes (ISGs) that are induced by IFN, double-stranded RNA (dsRNA), and viruses contain IFN-stimulated response elements (ISREs) in their promoters. The usual mechanism calls for inhibition of several steps of viral gene expression through the actions of several ISG products. ISG-encoded proteins have been chosen because of the diversity of their functions and their perceived importance in mediating antiviral actions. Protein kinase RNA regulated (PKR) was one of the earliest antiviral ISGs identified and is one of the most thoroughly investigated to date. PKR has been implicated in regulation of apoptosis both in the presence and absence of viral infection. The importance of PKR in mediating antiviral actions of IFN is manifested by the variety of strategies used by different viruses to evade PKR’s activation or action. The common structural features of adenosine deaminase acting on RNA (ADAR) family proteins include a dsRNA-binding domain and a conserved cytidine deaminase domain at the carboxyl terminus that contains highly conserved residues thought to be involved in catalysis.

This is an introductory chapter of the book Clinical Virology. The authors hope to convey the fascinating breadth and importance of the subject of clinical virology in this edition. This edition presents updated and improved information than the previous edition. Clinical virology is the domain of molecular biologists, geneticists, pharmacologists, micro-biologists, vaccinologists, immunologists, practitioners of public health, epidemiologists, and clinicians, both pediatric and adult. It encompasses events that include accounts ranging from epidemics impacting history and Jennerian vaccination to the identification of new agents and mechanisms of disease. In order to provide a comprehensive yet concise treatment of the diverse agents and diseases associated with human viral infections, this book is organized into two major sections. This chapter provides a table that lists the viruses known to infect humans. Many of the agents are primarily animal viruses that incidentally infect humans, such as herpesvirus B, rabies virus, the Arenoviridae, the Filoviridae, the Bunyaviridae, and many arthropod-borne viruses.

During the last 50 years, virologists have been able to select cell cultures that are susceptible to many commonly encountered viruses and environmental virologists have developed methods to detect very low numbers of viruses in various environments. This chapter reviews these methods and their practical use and describes basic quality control procedures to maximize their level of sensitivity. The main objective of the cultivation and assay of viruses is to optimize detection methods to a level where even a single infectious unit can be detected with confidence. Several methods for detection of viruses in environmental samples have been described: visualization of the virus by microscopy, detection of viral antigens, detection of viral nucleic acids, and detection of viral infectivity. The detection of infective viruses in environmental samples still relies mainly on cell culture as the method of choice. There are several sources for cell cultures that can be used in virology. Plaque assay is used for a very limited number of viruses and has the lowest sensitivity of the available methods. The main advantages of plaque assay are that each individual virus (or aggregate) forms a single plaque and that each plaque is rarely a mixture of several virus types. Viruses isolated by cell culture can be propagated further in cell culture and identified by a variety of methods, including electron microscopy, serum neutralization, molecular methods, and immunoassays.

This chapter reviews the microbiological risks of xenotransplantation as they currently exist, with the caveat that the technical tools of molecular biology are rapidly adding to our knowledge in leaps and bounds. The ethical issue for xenotransplantation from the microbiological aspect is the risk of introducing an unknown infectious agent into a naive human population versus the individual benefit of a life-giving organ transplantation and improved quality of life. There is a large database of information on pigs, from basic anatomy and physiology to specifics of their biochemistry and genome. Production of pigs in barrier facilities operated under very high standards of animal husbandry can consistently yield qualified-pathogen-free animals. The gibbon ape leukemia virus (GALV) behaves as an exogenous retrovirus, but DNA evidence points to the endogenous retrovirus of Mus caroli as the origin. Certainly, the expanding interest in pigs as organ donors has placed the subject of endogenous retroviruses, in particular the porcine endogenous retrovirus (PERV), front and center in the microbiological risk analysis of xenotransplantation. PERV mRNA has been identified at variable levels in all tissues examined, indicating that viral expression is not restricted. Transmission electron microscopy of tissues was negative, although virus-like particles (VLP) were detected in serum. Although the VLP did not bind antibodies against recombinant gag or whole virus, product-enhanced reverse transcriptase analysis produced positive results.