of Work: The preferential replication of HIV in Th2 and Th0 cells over Th1 cells has been recently proposed to occur during the development of AIDS. To address this question, we have infected human T helper (Th)clones, developed from different normal donors, with different HIV isolates and examined all differences in HIV fusion, entry, and infectivity. Our studies has demonstrated that human T cells and antigen- specific T cell clones express significant levels of several chemokine receptors on their surface which mediate T-cell trafficking, degranulation, and intracellular calcium mobilization as well as serving as co-receptors mediating HIV-1 entry into these cell populations. However, despite these differences in chemokine receptor expression, our studies have demonstrated that human Th0, Th1, and Th2 clones are all capable of being infected with the various T-, M-, and dual-tropic strains of HIV-1. HIV-1-infected Th1 clones are rapidly infected with HIV-1; however, they also exhibit a rapid (1-5 day) Fas-mediated apoptosis in vitro compared to infected Th2 clones (4-21 days). The increased expression of Fas ligand on the surface of Th1 but not Th2 clones post HIV-1 infection may possibly explain the more rapid turnover of this CD4+ T cell subset. Further examination of the various apoptotic signaling differences between human Th1 and Th2 clones revealed that all human Th1 but not Th2 cells are susceptible to activation- induced cell death (AICD). In addition, the majority of human Th1 clones expressed low levels of the anti-apoptotic protein, bcl-2, making them more susceptible to various apoptotic stimuli as well as HIV-1 induced T cell death. In contrast, human Th2 clones, the majority of which express high levels of endogenous bcl-2, were less susceptible to apoptotic stimuli and HIV-1- mediated cytopathic effects. Thus, the protection of bcl-2- expressing T cells from HIV-induced cell death suggests that apoptosis not only contributes to cell killing by HIV infection but may also permit the selective destruction of Th1 cells in the periphery leading to a systemic Th2 or Th3 response. The increased susceptibility of Th1 clones to HIV-mediated cell death suggests a major mechanism for HIV-induced immunosuppression in AIDS. We have found that Th1 and Th2 clones differ in their chemokine receptor expression profiles which appears to account, at least in part, for some cells increased susceptibility to HIV-1 infectivity. We believe that a Th1 to Th2 switch occurs during many long term chronic inflammatory disease states as well as within cancer and aging models which may influence a person?s susceptibility to HIV-1 infections as well as the number of circulating CD4+ cell numbers. We propose that antigen-specific CD4+ T helper cells and clones, without any exogenous influence from cytokines, derived from the peripheral blood of older individuals may be more permissive to T cell tropic HIV-1 infections compared to lymphocytes derived from younger donors. As AIDS in the elderly population continues to increase in number and as a percentage of all new AIDS cases, it has been hypothesized that T cells obtained from elderly may be more susceptible to HIV infection. The Clinical Immunology Section will attempt to directly examine this question. The objective of the proposed project is to further define the differences in T cell-, monocyte-, and dual- tropic HIV-1 replication in T cells derived from young and old donors as well as in human Th1 and Th2 clones. The relationship between T cell susceptibility to HIV-1 infectivity and apoptosis will be further examined. Finally, we will examine the signaling requirements of HIV-1 and HIV-1 proteins for virus interactions and infectivity of T cells.
