Mechanisms of Herpes Immune Evasion
“Viruses are smarter than humans”
Herpes simplex virus 1 (HSV-1) infects the cornea and then establishes latency in sensory neurons of the trigeminal ganglia (TG). Sporadic spontaneous reactivation of HSV-1 causes shedding of virus in tears with no clinical disease (asymptomatic) leading to spread of virus to other individuals. Virus reactivation can also cause recurrent eye disease (symptomatic) and may lead to vision loss. “Viruses are smarter than humans” by developing tricks to get around the immune system control. Work in The Laboratory of Cellular and Molecular Immunology (LCMI), at the University of California, Irvine has focused on understanding the molecular and cellular mechanisms used by HSV-1 to escape from the immune system. Specifically, we are interested in evaluating how the herpes latency associated transcript (HSV-1 LAT), the only gene expressed during the latent phase, interferes with the immune cell functions. One major area of ongoing work in the laboratory is to study how HSV-1 LAT contributes to virus immune evasion from CD8+ T cells following mouse and rabbit ocular infection. HSV-specific CD8+ T cells are involved in protective immunity against ocular herpes, possibly through a combination of corneal and peripheral nervous system antiviral effects.
We have a novel “humanized” HLA-A*0201 transgenic (HLA Tg) rabbit model of ocular HSV-1 that develops spontaneous reactivation, recurrent corneal disease and mounts specific CD8+ T-cell responses to human HSV epitopes. Although HLA Transgenic mice can also mount humanized CD8+ T-cell responses, they do not develop recurrent corneal disease. This HLA Tg rabbit model will allow us for the first time to test the hypothesis that spontaneous HSV-1 shedding and recurrent eye disease can be reduced by “protective” CD8+ T-cell responses through therapeutic immunization with asymptomatic human CD8+ T-cell epitopes and a therapeutic strategy that interfere with the HSV-1 LAT immuno-evasion mechanism. Validation of this hypothesis would have important implications for prevention of recurrent ocular disease.
Over the past 6 years, we have systematically determined that The HSV-1 Latency-Associated Transcript (LAT), the only viral gene that is abundantly transcribed during latency, increases reactivation. Recently we demonstrated that a novel immune evasion mechanism whereby the HSV-1 LAT promotes functional exhaustion (i.e., dysfunction) of HSV-specific CD8+ T cells in latently infected TG, resulting in increased virus reactivation. Additional efforts are now focused on understanding how HSV-1 LAT regulates HSV-specific CD8+ T cell immunity within the TG following viral infection. For instance we sought to determine if this impairment might involve LAT indirectly interfering with DC maturation. The subsequent reduced immunosurveillance by TG-resident CD8+ T cells may contribute to the known increased reactivation associated with LAT expression.