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Pathogenesis of herpes simplex virus type 1 infection

INTRODUCTION

Herpes simplex virus type 1 (HSV-1) is a member of the family of herpesviruses that includes HSV-1, herpes simplex virus type 2 (HSV-2), cytomegalovirus, Epstein Barr virus, and human herpesviruses 6, 7, and 8. This family of viruses is further classified into three subfamilies that include alpha, beta, and gamma herpesviridae. HSV-1 and HSV-2 belong to the alpha herpesviridae subfamily and the genus Simplexvirus, which are characterized by their variable host range, short replication cycle, and the ability to destroy infected cells and establish latent infection [1]. While members of the herpesvirus family share certain structural features, the spectrum of clinical illness induced varies considerably.

The pathogenesis of infection due to HSV-1 and viral mechanisms to avoid the humoral and cellular components of the immune system will be reviewed here. The epidemiology, clinical manifestations, diagnosis and treatment of infection by HSV-1 and other members of the herpesvirus family are discussed separately. (See "Epidemiology of herpes simplex virus type 1 infection" and "Clinical manifestations and diagnosis of herpes simplex virus type 1 infection" and "Treatment of herpes simplex virus type 1 infection in immunocompetent patients" and "Prevention of herpes simplex virus type 1 infection in immunocompetent patients".)

STRUCTURE AND LIFE CYCLE OF HSV-1

HSV-1 is a double-stranded DNA-enveloped virus, with a central core containing the viral DNA, an inner core surrounded by envelope derived from both host cellular membranes and viral glycoproteins, and an icosahedral capsid composed of viral proteins [1]. Between the capsid and the envelope lies the tegument, a proteinaceous structure containing two proteins important in the pathogenesis of HSV-1 infection, alpha-transinducing factor (alpha-TIF) (aka: VP16 and Vmw65) and virion host shut-off protein (VHS). VP16 is a transcriptional activator protein that forms a complex with host cell factor (HCF), which localize within the nucleus. These proteins, together with the host transcription factor, octamer-binding protein 1(OCT1), enable the recruitment of other host factors that stimulate transcription of immediate-early (IE) viral gene products [2].

Viral glycoproteins — Alpha-TIF activates the viral replication cascade, and VHS shuts off host cell macromolecular synthesis (see below) [3,4]. Approximately 1,000 molecules of alpha-TIF and 200 copies of VHS are present in the tegument and packaged in the virion [1,5]. Thus, these proteins can act early as virus particles enter the cells and uncoat. The viral glycoproteins embedded in the lipid envelope mediate attachment to host cell receptors, fusion of viral and host cell membranes, and envelopment and emergence of virus as newly formed nucleocapsids bud from host cell nuclei [6]. These glycoproteins are also the major targets of humoral and cellular immune responses and viral immune escape mechanisms by binding both complement and anti-HSV IgG molecules [1].

Viral replication — Viral replication takes approximately 24 hours and begins with the attachment of viral glycoproteins to cell-surface receptors, including glycosaminoglycan (GAG) heparan sulfate and the immunoglobulin-like cellular receptors (designated nectin1-alpha and delta and nectin2-beta) [7,8]. Glycoproteins gC and gB interact with GAG heparan sulfate, while gD provides a stable attachment to cellular receptors. Glycoprotein gC also binds complement protein C3b and inhibits complement activation [9]. HSV strains with mutations in the gC gene are more susceptible to neutralization by human serum.

                   

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Literature review current through: Sep 2014. | This topic last updated: Dec 16, 2013.
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