Although much is now known about HIV-1 infection and its interaction with the host immune system, investigators have been unable to apply this knowledge to the development of an effective vaccine. Longitudinal study of long-term non-progressors, asymptomatic persons who have been infected with HIV-1 for over ten years yet have maintained normal CD4+ T-lymphocyte counts and low viral loads, and rapid progressors, persons who have advanced to AIDS within four years of infection, may provide needed insight into the control of viral replication in populations at risk. Issues to be explored include: a) determination of the breadth and specificity of the initial CTL immune response in persons with non- progressive and rapidly progressive HIV-1 infection and correlation of this CTL response with other immunologic and virologic parameters, (b) determination of the fate of clonal CTL responses in persons with progressive and non-progressive disease, and (c) comparison of the ability of CTL clones from progressors and non-progressors to inhibit autologous HIV-1 replication. Blood samples obtained at six month intervals from 6 persons with non- progressive infection and 6 persons with progressive infection have been obtained from the MACS. PBMC from these individuals will be stimulated with vaccinia expressed recombinant HIV-1 proteins and evaluated in standard chromium release assays for the presence of HIV-specific CTL. Additionally, HIV-specific CTL clones will be obtained and their peptide epitopes mapped. Autologous viral sequences and HIV-specific antibody responses will also be determined and related to CTL responses and rate of disease progression. The fate of clonal CTL responses in these persons will be determined by analyzing the presence of specific TCR transcripts over time. The gain or loss of a TCR will be correlated with functional studies of CTL activity over time. Inhibition of autologous virus replication by CTL will be explored by acute infection of autologous CD4+ T-lymphocytes which will then be cocultured with CTL clones. Supernatant will be harvested at intervals for ELISA p24 measurement and the degree of inhibition over time will be determined. Better understanding of the role of host immunity in controlling HIV-1 infection will have potential application in future therapeutic strategies for immunotherapy and vaccine design.
