Cytotoxic T Cell Responses to HSV in HIV Infected Persons

Lawrence Corey, MD

While long recognized as a prevalent infection among HIV+ persons, it is only within the last few years that mucosal herpes simplex virus (HSV) infections have become recognized as important factors in the transmission and clinical progression of HIV (1) . HIV virions are shed in genital lesions and in subclinical ulcerations (2) . The high frequency of HSV reactivation (>50% of days) and the multiple anatomic sites of reactivation in HIV+ persons influence HIV-1 RNA levels and subsequent disease progression (3-5) . Our initial studies of the immune response to HSV among HIV+ persons suggested that those with low frequencies of HSV-specific CD8+ T cell precursors (pCTL) as measured by limiting dilution analysis (LDA) had more severe HSV episodes than those who had high precursor frequencies (6) . In the initial funding period of this proposal, we proposed the hypothesis that this was likely due to inadequate CD4+ T cell help, and that like other opportunistic infections (OIs), increasing memory CD4 + T cell responses associated with HAART therapy would alter HSV reactivation rates. As described in detail below, we were surprised to see that this was not the case; HAART therapy appears to have no discernible influence on HSV reactivation rates despite being associated with increases in HSV-specific CD4+ T cell responses. However, what has consistently emerged from both cross-sectional and longitudinal studies is the association between low numbers of pCTL and frequent HSV reactivation. This renewal is directed at the relationship between HSV-specific CD8+ T cell responses and mucosal reactivation rates of HSV.

Specific Aim 1. Hypothesis: Mucosal HSV reactivation rates are inversely proportional to the quantitative memory CD8+ T cell response to HSV. As HSV infections antedate HIV acquisition, we will evaluate this hypothesis among HIV+ persons with recent HIV acquisition who have relatively preserved CD4+ T cell help as well as among HIV-negative persons with newly acquired primary HSV infection. We will utilize a variety of recently developed techniques to quantitate CD8+ T cell responses to whole virus, preparations of virus that contain virion input proteins, selected individual HSV proteins, overlapping peptides to virion and tegument proteins and recently developed HLA-A2 tetramers.

Specific Aim 2. Hypothesis: Persons with high numbers of circulating HSV-specific memory CD8+ T cells mount a more vigorous mucosal CD8+ T cell response to HSV infection than those with low numbers of circulating CD8+ T cell responses. Lesion infiltrating T cell responses will be compared among persons with low versus high frequencies of circulating HSV-specific CD8+ T cells and with prolonged and frequent versus short and infrequent mucosal HSV reactivations. The in vivo amplification of T cells that occurs with HSV reactivation allows us to directly sample T cells from lesions and quantitate the association between HSV-specific T cells and in vivo viral replication.

Specific Aim 3. Hypothesis: HSV-specific CD8+ T cells from HIV+ persons exhibit altered killing pathways as compared to HSV specific CD8+ T cells from HIV-negative persons . These studies will explore if HSV-specific killing and/or chemokine releases are altered in herpetic lesions from HIV+ as compared to HIV-negative p ersons.

Recent Peer Reviewed Publications:

Posavad CM, Wald A, Hosken N, Huang ML, Koelle DM, Ashley RL, Corey L.   T cell immunity to herpes simplex viruses in seronegative subjects: silent infection of acquired immunity?   J Immunol 2003; 170:4380-88.

Posavad CM, Huang ML, Barcy S, Koelle DM, Corey L.   Long term persistence of herpes simplex virus-specific CD8+ CTL in persons with frequently recurring genital herpes.   J Immunol 2000; 165:1146-52.

Posavad CM, Koelle DM, Corey L.   Tipping the scales of herpes simplex virus reactivation: The important responses are local.   Nature Med 1998; 4:381-82.

Posavad CM, Koelle DM, Shaughnessy MF, Corey L.   Severe genital herpes infections in HIV-infected individuals with impaired HSV-specific CD8+ CTL responses. Proc National Acad Sci USA 1997 94:10289-94.