CD8+ T cells have been shown to suppress replication of HIV-1 by a non-lytic mechanism. However, very little is known about the mechanism responsible for such HIV-1 suppression and the identity of the suppressive factor. Suppression of HIV-1 seems to be at the level of viral transcription. The clinical significance of this suppressive activity is suggested by the reduction of antiviral activity of CD8+ T cells during the development of disease. Recently the investigator has shown that the level of antiviral activity of CD8+ T cells depends upon the phenotypes of HIV-1 present in infected target CD4+ T cells. The investigator s overall objective is to determine the mechanism of CD8+ T cell suppression by characterizing the suppressive factor and by identifying the target region of HIV-1 genome required for CD8+ T cell mediated antiviral activity. Furthermore, he will investigate the role of CD8+ T cell suppressive activity in HIV-1 pathogenesis using a newly developed semiquantitative assay for the factor.
The specific aims of the project are: 1. To define the target region of HIV-1 genome responsible for CD8+ T cell suppression. LTR-cat constructs carrying progressive deletions in the LTR region from the 5 and replication competent HIV-1 variants carrying deletions in the LTR region and U3 region will be used to map the minimum target sequences required for suppressive activity. 2. To determine the HIV-1 genome region responsible for phenotype dependent differential suppressive activity. Intrastrain recombinants between two molecularly cloned infectious viruses with diverse phenotypic properties will be used to map the region responsible for differential suppressive activity. 3. To isolate and purify the suppressive factor from the culture supernatant CD8+ T cells by standard biochemical purification techniques. 4. To elucidate the role of CD8+ T cell suppression in pathogenesis. Longitudinally isolated CD8+ T cells from three groups of subjects from the multicenter cohort study will be included: a) subjects who are long-term non-progressors with stable CD4 T cells; b) subjects who are rapid progressors with a sharp decline in CD4 T cells usually developing AIDS within 3 years; and c) subjects who had a period of stable CD4 cells followed by a sharp decline (inflection point) in CD4 T cells. The results from this study are intended to provide valuable information on the mechanism of CD8+ T cell suppression of HIV-1 and its role in pathogenesis.
| Chen, Y; Dampf, D; Chen, M et al. (2000) Dependence of CD8+ T-cell-mediated suppression of HIV type 1 on viral phenotypes and mediation of phenotype-dependent suppression by viral envelope gene and not by beta-chemokines. AIDS Res Hum Retroviruses 16:117-24 |
