Approximately 16% of Americans aged 14-49 are currently seropositive for Herpes simplex virus type 2 (HSV- 2) and worldwide, 23 million new infections occur each year. Infection of neonates and immune compromised individuals results in serious morbidity or death. Further, HSV-2 infections increase the risk of acquisition of HIV. Immunization would be the most effective approach to control HSV-2, but prophylactic vaccines that elicit systemic immune responses against HSV-2 have failed in clinical trials. Preclinical studies with HSV-2 infected mice and humans have suggested that the presence of virus-specific T cells at the site of viral infection in the genital epithelia may be critical for effectve protection of the genital epithelia. These cells are strategically located to protect against re-infection and to interfere with HSV-2 shedding in the genital tract thereby impacting HSV-2 transmission. Mathematical models of the interaction of these cells with the reactivated virus suggest that genital-resident memory T cells may determine the duration of HSV-2 shedding and that stimulating these cells therapeutically may impact virus shedding; however, a clear demonstration of this protective role is lacking. Understanding the function of these cells in modulation of HSV-2 shedding and how to induce these cells with vaccines requires an animal model that accurately reflects the pathogenic events of HSV-2 as they occur in humans. Guinea pigs are the only common laboratory animals that experience spontaneous reactivation and virus shedding events during latent HSV-2 infection that are similar to those experienced by infected humans and represent the best model to test hypotheses of immune modulation of HSV-2 recurrent shedding. Using this model, our central hypothesis is that these cells play a critical role in modulating the frequency and/or magnitude of HSV-2 shedding and in limiting the extent of vaginal epithelium infection during HSV-2 shedding events. Further, the magnitude of this cell population can be effectively enhanced by therapeutic immunization with a replication defective HSV-2 vaccine. Our long term goal is to develop therapeutic vaccines that will enhance the number and function of HSV-specific genital tract resident T cells to protect the female genital mucosa against recurrent disease and control recurrent HSV-2 shedding in individuals that do become infected, therefore impacting HSV-2 transmission. The objective of this application is to understand the impact of virus-specific genital-resident T cells on virus shedding after reactivation of HSV- 2 from latency.
Aim 1 will determine the role of genital-resident, HSV-specific memory T cells in modifying the frequency and/or magnitude of HSV-2 shedding following natural HSV-2 reactivation.
Aim 2 will determine if the efficacy of therapeutic immunization in modulating recurrent disease and virus shedding can be optimized by specifically enhancing the magnitude of HSV-specific genital-resident T cell populations. This work is significant because understanding the role of virus-specific T cells residing in the genita tract at the site of HSV-2 shedding will be critical for development of therapeutic vaccines to reduce HSV-2 transmission.
Genital HSV-2 infection of women results in an increased risk of acquisition of HIV and the potential for infection of newborns by contact with HSV-2 containing secretions from the infected reproductive tract. Induction of strong cell-mediated immunity in the genital tract of infected individuals by therapeutic vaccines would likely reduce the amount of virus shed by HSV-2 seropositive women and decrease the risk of transmission. The results of these proposed studies will be critical for understanding the role of genital tract-resident memory T cells in modulating HSV-2 recurrent shedding and will form the basis for future efforts to impact virus transmission by modulating HSV-2 shedding using therapeutic vaccines.
| Veselenak, Ronald L; Milligan, Gregg N; Miller, Aaron L et al. (2018) Transcriptional Analysis of the Guinea Pig Mucosal Immune Response to Intravaginal Infection with Herpes Simplex Virus Type 2. Virology 518:349-357 |
| Perry, Clarice L; Banasik, Brianne N; Gorder, Summer R et al. (2016) Detection of herpes simplex virus type 2 (HSV-2) -specific cell-mediated immune responses in guinea pigs during latent HSV-2 genital infection. J Immunol Methods 439:1-7 |
