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Introduction: retroviruses, DNA viruses, and prions
Leigh Zerboni, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA,
Ann M. Arvin, Department of Pediatrics and Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA
Varicella-zoster virus (VZV) is a neurotropic human herpesvirus that causes varicella, which is commonly known as chicken pox, as the primary infection in susceptible individuals. In the healthy host, varicella is usually a mild, self-limiting febrile illness characterized by a generalized, pruritic vesicular rash (Figure 12.1A). Like other alphaherpesviruses, VZV gains access to sensory ganglia of the peripheral nervous system during primary infection and establishes lifelong persistence at these sites. VZV reactivation from latency causes herpes zoster, called “shingles,” and is associated with a vesicular rash localized to one of the cutaneous dermatomes of the face, trunk, or extremities (Figure 12.1B). The dermatomal rash reflects the region of skin innervated by the cranial nerve or dorsal root ganglion where reactivation is occurring. VZV is highly contagious and is maintained in the human population by close contact with individuals who have varicella or herpes zoster. Both primary and recurrent VZV infections are more severe in immunocompromised patients because resolution requires an effective cell-mediated immune response. Antiviral drugs that inhibit VZV replication are effective in most high-risk patients with varicella or herpes zoster. VZV is the only human herpesvirus for which vaccines that prevent or modify the severity of primary and recurrent infections have been developed. These vaccines are made from the VZV/Oka strain, attenuated by passage in vitro.
While the clinical manifestations of varicella and herpes zoster are well-documented, knowledge about the mechanisms of VZV pathogenesis in the human host is limited because primary and recurrent infections are rarely fatal and VZV infection is highly species-specific for the human host.
Ann Arvin, Department of Pediatrics and Microbiology and Immunology, Stanford University School of Medicine,
Patrick Moore, Molecular Virology Program, University of Pittsburgh Cancer Institute Hillman Cancer Center,
Richard Whitley, Department of Pediatrics, University of Alabama at Birmingham
VZV is a human alphaherpesvirus that causes varicella (chickenpox) as the primary infection and establishes latency in sensory ganglia. VZV reactivation results in herpes zoster (shingles). During the course of varicella and zoster, VZV infects differentiated human cells that exist within unique tissue microenvironments in humans. The tropism of VZV for skin is the most obvious clinical manifestation of VZV infection, producing the vesicular cutaneous lesions that are associated with varicella and zoster. The site of initial VZV infection in naïve hosts is thought to be mucosal epithelial cells of the upper respiratory tract. Entry is presumed to follow inoculation of the respiratory epithelium with infectious virus transmitted by aerosolized respiratory droplets or by contact with virus in varicella or zoster skin lesions (Arvin, 2001a; Grose, 1981). VZV in respiratory or conjunctival mucosal cells has the opportunity to interact with and infect local immune system cells and those in adjacent lymphoid tissues. Trafficking of infected peripheral blood mononuclear cells (PBMC), which appear to be predominantly T-cells, to the skin is thought to give rise to crops of cutaneous vesicles. Skin lesions contain VZV material associated with necrotic debris and, unlike virus grown in vitro, cell-free, infectious particles are detected in vesicular fluid (Williams et al., 1962). The life cycle of VZV is completed upon its transmission to a susceptible host from an individual with varicella, or it can be postponed for decades by establishing latency in neurons and transmitting to future generations during episodes of zoster.
Pathogenesis, clinical disease, host response, and epidemiology: VZU
Ann Arvin, Departments of Pediatrics and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA,
Allison Abendroth, Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Westmead, NSW, Australia
Varicella zoster virus (VZV) like the other herpesvirus family members is a highly successful and ubiquitous human pathogen. In order for VZV to persist in the human population, the virus has evolved strategies to avoid immune detection and potentially promote viral pathogenesis. We have demonstrated that VZV encodes two separate immune evasion strategies by specifically down-regulating cell-surface MHC class I (Abendroth et al., 2001a) and inhibiting the up-regulation of interferon-γ-induced MHC class II expression (Abendroth et al., 2000) during productive infection of primary human foreskin fibroblasts (HFFs). Given that VZV appears to evade host recognition by T-cells during the prolonged, 10–21 day incubation period, viral genes encoding immunomodulatory proteins are likely to delay the initial clonal amplification of VZV specific CD4+ and CD8+ T-lymphocytes and at least transiently enhance the ability of VZV to replicate at cutaneous sites. Recently we have studied the interaction of VZV with human dendritic cells (DCs) and T-lymphocytes. VZV has the ability to infect immature DCs and transfer virus to T-lymphocytes (Abendroth et al., 2001b). VZV also readily infects tonsil T-cells (Ku et al., 2002). The analysis of VZV interactions with T-cells during viral pathogenesis is described in Chapter 37. These capacities of VZV to infect DC and T-cells provide new models of viral dissemination during primary and recurrent VZV infections. Further studies assessing mature DCs have revealed a third immune evasion mechanism for VZV whereby the virus is able to productively infect a specialized immune cell (representing the most potent antigen presenting cell type), and in doing so impairs its ability to function properly.
Ann Arvin, Professor of Pediatrics, Microbiology, and Immunology, Stanford University,
Gabriella Campadelli-Fiume, Professor of Microbiology and Virology, University of Bologna, Italy,
Edward Mocarski, Professor of Microbiology and Immunology, Emory University,
Patrick Moore, Professor of Molecular Genetics and Biochemistry, University of Pittsburgh,
Bernard Roizman, Professor of Molecular Genetics, Cell Biology, Biochemistry, and Molecular Biology, University of Chicago,
Richard Whitley, Professor of Pediatrics, Microbiology, Medicine, and Neurosurgery, University of Alabama Birmingham,
Koichi Yamanishi, Professor of Microbiology, Osaka University, Japan
Diseases caused by the human herpesviruses were recognized by the earliest practitioners of medicine. Hippocrates, Celsus, Herodotus, Galen, Avicenna and others described cutaneous lesions typical of infections caused by herpes simplex viruses (HSV) 1 and 2, and varicella-zoster virus (VZV). ‘Herpes,’ the family name of these viruses, is traced to the Greek term for lesions that appeared to creep or crawl over the skin. Among the duties of John Astruc, physician to King Louis XIV, was to understand the diseases of French prostitutes, in Latin, the ‘Puellae publicae’, which led to his description of herpes genitalis. Distinguishing between genital herpes and syphilis was an obvious concern in this social context as it is now. The modern scientific investigation of HSV can be dated to the work of Gruter, who first isolated the virus and demonstrated its serial transmission in rabbits. During the 19th century, experiments in human subjects showed that HSV and VZV could be transmitted from fluid recovered from HSV and VZV lesions. Demonstrating that Koch's posulates were fulfilled was important but arguably the truly revolutionary discovery about the herpesviruses was made by Andrews and Carmichael in the 1930s who showed that recurrent herpes labialis occurred only in adults who already had neutralizing antibodies against HSV.
This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.