Transmission of HIV infection occurs predominantly through mucosal routes, and it is essential that HIV vaccine regiments stimulate protective immunity in the mucosal compartment. In addition to local antibody production, both CD8+ CTL, the major effector cells in viral resistance, and CD4+ T helper cells will likely play a critical role in HIV mucosal immunity. Investigations of mucosal immunity in HIV infection have been directed primarily to the detection of local antibody responses, and little is known about cellular immune response. Analysis of the requirements to achieve mucosal protection in human vaccine trials has been limited by lack of systematic method to collect adequate specimens as well as the availability of vaccine regimens that can stimulate detectable mucosal response. Consequently, the overall goal of the proposed study is to identify the specific cellular components in the genital and rectal mucosa that participate in HIV immune surveillance and thus may be important to elicit by HIV preventive vaccines. Initial efforts will be directed toward the analysis of specimens from the mucosal regions of HIV-infected individuals for analysis of in vitro cellular responses. Mucosal sites to be examined in this project include cervical brushings and biopsies, rectal biopsies, and semen. Subsequent studies will focus on the mucosal HIV-specific responses elicited by AVEG candidate vaccines HIV-uninfected volunteers. Such studies will complement the mucosal antibody studies in Project II of the collaborative proposal. The major aims of this project will be identify and characterize the HIV- specific CTL and helper T cells in the mucosal sites of HIV-infected persons and HIV-uninfected vaccine recipients. Mucosal CTL responses to HIV gene products will be amplified by a variety of stimulation and cloning techniques, and the MHC restriction patterns, cell phenotypes and capacity to recognize and lyse HIV-infected cells will be analyzed. In selected subjects, the precursor CTL frequency in the mucosal compartment will be measured and correlated with local HIV genomic copy number to determine the role of these effector cells in viral clearance. Companion studies will characterize the T helper responses in the mucosal region, with analysis of antigen recognition and cytokine induction profiles. Collaborative studies will compare the T cell effector and helper responses with the local production of mucosal immunoglobulin. These investigations will provide insight into the components of mucosal immunity that may be beneficial to elicit with HIV vaccines and will advance the technology required to detect these responses following immunization.
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