This application is submitted in response to RFA AI-94-010. We propose to establish a consortium of laboratories to co-ordinate virological, immunological, molecular biological, and genetic investigations of the biological basis of progression of HIV infection from seroconversion to AIDS. This will be done using the clinical and repository resources of the Multicenter AIDS Cohort Study (MACS). Specifically, in order to identify the immunologic and virologic mechanisms which may be involved in progression to disease or in long-term stability and non-progression, we propose to perform concurrent and non-concurrent prospective cohort studies of three groups of HIV+ MACS participants, who have been selected because of their different clinical responses to HIV infection: 1) no decline of CD4+ lymphocytes (i.e., counts > 8O0/microliters) despite at least 10 years of HIV infection (high stable group), 2) stable CD4+ lymphocyte counts for 4-5 years after an initial moderate decline to the range of 350-500/microliters (low stable group) and 3) recent seroconverters with CD4+ lymphocyte levels similar to group I now but likely to decline significantly during the study period. Using specimens collected from these study participants every 3 months (in the concurrent prospective study) or every 6 months (in the nonconcurrent prospective study), we will test the hypotheses that 1) viral load and genetic diversity, as well as host genetics and immune response to HIV, early in the infection have a major impact on the rate of progression of HIV disease; 2) low viral load and disease stability are maintained by cytotoxic T lymphocytes and other immunological effector mechanisms; and 3) a final common pathway of disease progression begins approximately 2 years prior to AIDS. These hypotheses will be tested by measuring viral load (i.e., levels of unspliced (gag) RNA in PBMC and plasma measured by quantitative PcR, and proviral DNA PBMC by quantitative PCR and in situ PCR), viral genetic diversity and phenotypic variation (measured by heteroduplex mobility assay and heteroduplex tracking assay), host immune response (activity of effector and memory cytotoxic T lymphocytes (CTL), CD8+ lymphocyte-mediated suppression of HIV replication, and neutralizing antibodies against autologous viruses. These critical data will be correlated with progression of disease (decline or stability of CD4+ lymphocyte counts, development of HIV-related symptoms) of the subjects studied. The data obtained, and the repository which will be established of biological samples, HIV isolates, and other materials, will be important in unraveling the mechanisms by which some HIV+ gay men are able to prevent progression of HIV disease, and thus will be important for development of drugs and vaccines against HIV.
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