This proposal is directed at discovering the mechanism(s) by which human immunodeficiency virus (HIV) causes severe recurrent herpes simplex virus (HSV) infection. Recurrent HSV disease has a remarkable spectrum of disease severity in HIV-seropositive people. Recent studies indicate that people with both early and late HIV infection experience longer, and more frequent, asymptomatic and symptomatic HSV reactivation episodes as compared to HIV-seronegative people. PBMC immune responses to HSV have not been correlated with disease severity. To address host responses at cutaneous HSV recurrence sites, we have developed methods to study HSV- specific lesion-infiltrating T cells. This infiltrate is predominantly CD4+ in HIV-seronegative people. A ThO-like pattern of local cytokine responses and T cell receptor (TCR) gamma-delta+ cells reactive with HSV have also been detected. We hypothesize that quantitative or qualitative defects in local HSV-specific responses are associated with worsening of HSV disease, and propose extension of our studies to HIV-seropositive people. Preliminary studies have utilized specimens from HIV-infected persons with mild HSV disease. Both CD4+ and CD8+ HSV-specific lymphocytes were recovered, with a possible increase in CD8+,T cells from patients with lower CD4 cell counts. Infiltration of HSV lesions by specific T cells was preserved in patients who had lost PBMC responses to HSV antigen. The recovery of TCR gamma-delta+ cells from lesions has been lower from HIV-infected than from HIV-seronegative persons. Cytokine measures suggest a possible shift to a Th2-like pattern. In addition to changes in the antigen-specific T cell infiltrate, effects of HIV infection may include,apoptosis or replication of HIV in HSV-specific CD4+ cells activated within lesions. Lesion-resident antigen presenting cells may also be effected. The goals of this proposal are 1) to characterize lesion immune responses to HSV in HIV-infected persons, 2) to determine if HSV-specific CD4+ T cells within recurrent HSV lesions show evidence of apoptosis or HIV replication, 3) to evaluate cytokines patterns within recurrent HSV lesions from HIV-infected persons, and 4) to measure the ability of cutaneous APC from HIV-infected persons to present antigen to HSV-specific T cells. We will evaluate HIV-infected patients both with and without severe HSV disease, and compare our findings to responses from HIV-seronegative people. HSV is a unique OI because antigen-specific CD4+ T cells preferentially and predictably localize to an accessible site. The presence of HSV disease in many HIV-seronegative people, in contrast to some other HIV-related OI, provides an optimal control group. Recurrent HSV infection therefore presents a timely opportunity to evaluate the mechanism(s) by which HIV-induced immunosuppression leads to a clinically significant opportunistic infection.
Showing the most recent 10 out of 11 publications
