What is the pathophysiology of herpes simplex virus (HSV) infection?

Updated: Mar 17, 2020
  • Author: Sean P McGregor, DO, PharmD; Chief Editor: William D James, MD  more...
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Intimate contact between a susceptible person (without antibodies against the virus) and an individual who is actively shedding the virus or with body fluids containing the virus is required for herpes simplex virus (HSV) infection to occur. Viral shedding occurs during the primary infection, during subsequent recurrences, and during periods of asymptomatic viral shedding. Contact during these periods must involve mucous membranes or open or abraded skin. Following exposure, the primary infection of HSV is established at the site of contact. Here, the viral envelope is fused with the cellular membranes of the skin and mucous membranes and HSV DNA is incorporated into the nucleus. [1]  HSV glycoprotein C protects the viral envelope and aids in viral entry. [2] Recognition of HSV DNA by Toll-like receptors results in the activation of the innate and adaptive immune systems and production of interferon gene products. [1] Viral suppression of host cell immune responses and subsequent evasion of the immune system is accomplished via a complex interplay between HSV virion protein products and the immune system. Specifically, the HSV protein, virion host shutoff (VHS), is produced in the early stages of infection to suppress host cell responses. [1] Additionally, glycoprotein C binds to complement C3b, inhibiting complement-mediated immunity and plays a role in inhibiting antibody neutralization. [2]  HSV then invades and replicates in neurons as well as in epidermal and dermal cells. Virions travel from the initial site of infection on the skin or mucosa to the sensory dorsal root ganglion, where latency is established. The latent state is established by silencing of the HSV genome in neurons, and reactivation can occur during periods of stress.

Viral replication in the sensory ganglia leads to recurrent clinical outbreaks. These outbreaks can be induced by various stimuli, such as trauma, ultraviolet (UV) radiation, extremes in temperature, stress, immunosuppression, surgical and laser procedures, or hormonal fluctuations. HSV-specific CD8+ T cells appear to play an important role in controlling recurrent infections and reactivation. [3] CD8+ T cells are primed and recruited by innate and adaptive immune responses during the primary infection. The chemokine receptors, CXCR3 and CCR10, have been found to be up-regulated in HSV-specific CD8+ T cells and may contribute to homing mechanisms and control of inflammation during periods of reactivation. [3]

HSV-1 reactivation occurs most efficiently from trigeminal ganglia (affecting the face and the oropharyngeal and ocular mucosae), while HSV-2 has a more efficient reactivation in the lumbosacral ganglia (affecting the hips, buttocks, genitalia, and lower extremities). The clinical difference in site-specific reactivation between HSV-1 and HSV-2 appears to be due, in part, to each virus establishing latent infection in different populations of ganglionic neurons. [4]

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