Genital Herpes: Insights into Sexually Transmitted Infectious Disease

Abstract

Etiology, transmission and protection: Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections with recurring manifestations throughout the lifetime of infected hosts. Currently no effective vaccines or prophylactics exist that provide complete protection or immunity from the virus, which is endemic throughout the world. Pathology/Symptomatology: Primary and recurrent infections result in lesions and inflammation around the genital area and the latter accounts for majority of genital herpes instances. Immunocompromised patients including neonates are susceptible to additional systemic infections including debilitating consequences of nervous system inflammation. Epidemiology, incidence and prevalence: More than 500 million people are infected worldwide and most reported cases involve the age groups between 16-40 years, which coincides with an increase in sexual activity among this age group. While these numbers are an estimate, the actual numbers may be underestimated as many people are asymptomatic or do not report the symptoms. Treatment and curability: Currently prescribed medications, mostly nucleoside analogs, only reduce the symptoms caused by an active infection, but do not eliminate the virus or reduce latency. Therefore, no cure exists against genital herpes and infected patients suffer from periodic recurrences of disease symptoms for their entire lives. Molecular mechanisms of infection: The last few decades have generated many new advances in our understanding of the mechanisms that drive HSV infection. The viral entry receptors such as nectin-1 and HVEM have been identified, cytoskeletal signaling and membrane structures such as filopodia have been directly implicated in viral entry, host motor proteins and their viral ligands have been shown to facilitate capsid transport and many host and HSV proteins have been identified that help with viral replication and pathogenesis. New understanding has emerged on the role of autophagy and other innate immune mechanisms that are subverted to enhance HSV pathogenesis. This review summarizes our current understanding of HSV-2 and associated diseases and available or upcoming new treatments.

Keywords: antivirals; herpes simplex virus; viral glycoproteins; viral latency; virus entry.

Figure 1. FIGURE 1: Schematic of HSV-1/HSV-2 lytic infection.

The HSV-1/HSV-2 virion recognizes and attaches to the heparan sulfate proteoglycan via glycoproteins on the viral envelope. By a process called ‘surfing’, the virus particles can travel along filopodia-like membrane extensions to reach the surface of the cell. On the surface of the cell, viral capsid penetration can occur by fusion of envelop with the plasma membrane (I), or alternatively by endocytosis of enveloped virions with eventual fusion of the envelope with a vesicular membrane (II). In either case, gD on the virus envelope is required via its interaction with one of the receptors (shown in red): herpesvirus entry mediator (HVEM) or nectin-1 and-2. In the cytoplasm, the capsid (brown) travels to the nucleus where the viral DNA is released. Multiple rounds of replication result in multiple copies of viral DNA and other components that get packaged and assembled in the nucleus. During egress, the newly assembled capsid gets its primary envelope at the peri-nuclear membrane, which is lost during egress from the outer nuclear membrane. Naked capsid travels through the cytoplasm where it receives the tegument and the viral envelope (presumably from the Golgi or the ER). Heparanase (denoted as pink spots) is an enzyme that was recently described in aiding viral egress. The enzyme cleaves of cell surface heparan sulfate (dotted black) which clears the path for the virus to exit the cell.

Figure 2. FIGURE 2: Schematic of Primary Infection and Reactivation.

Primary infection occurs when a host is exposed to the virus for the first time. When a person is exposed to HSV, the virus infects the epithelial cells. Depending on the immune system of the host, lytic infection leads to virus shedding that can cause symptoms such as ulcers or remain asymptomatic. After lytic infection, the virions reach the nerve endings and through a retrograde transport, reach the sacral ganglion where it establishes latency till the life of the host. Recurrent infections occur when the virus gets reactivated due to stress, environmental conditions and other unknown factors. Reactivation causes the virus from the sacral ganglion to travel to the site of primary infection or high nerve endings via an anterograde fashion where virus shedding can cause symptoms or remain asymptomatic depending on the host immune system.