The course of human immunodeficiency virus (HIV)-1 infection is controlled by host factors that are components of the anti-viral immune response. In particular, it seems that cell-mediated immunity involving CD8+ T cells play a key role to control infection by via cytotoxicity and via the production of soluble non cytotoxic HIV-suppressor factors that have not been analyzed in detail. Three beta C-C chemokines released by activated CD8+T cells (RANTES, MIP-1 alpha, and MIP-1 beta) are the major factors responsible for the soluble suppressor activity against macrophage-tropic HIV-1 isolates. Cross sectional studies of HIV-1+ individuals performed by the applicant have indicated that production of MIP-1 alpha and beta by freshly isolated, primary CD8+ T cells correlates inversely with HIV-1 disease progression as defined by a number of parameters. Based on this, the hypothesis is proposed that progression of HIV-1 disease is related to quantitative or qualitative changes in CD8+ T cell subset(s) that reduce the production of suppressive beta chemokines by activated suppressor cells.
Two specific Aims are proposed to test this hypothesis: 1) to define the CD8+ T cell subsets that can be activated to produce HIV-suppressive beta chemokines, and 2) to define quantitative and qualitative changes in the CD8+ T cell subsets during the course of HIV-1 disease progression that lead to altered chemokine expression by activated cells. Correlation of the magnitude of any observed impairment with disease progression will validate the hypothesis.
| Cocchi, F; DeVico, A L; Yarchoan, R et al. (2000) Higher macrophage inflammatory protein (MIP)-1alpha and MIP-1beta levels from CD8+ T cells are associated with asymptomatic HIV-1 infection. Proc Natl Acad Sci U S A 97:13812-7 |
