Most HIV-I infections are initiated by M-tropic strains which subsequently switch to predominantly T-tropic HIV infection during the rapid progression of AIDS. A better understanding of the biological basis of the switch from M-tropic to T-tropic HIV-infection will be significant in our ability to contain viral infection, early in its asymptotic state. We wish to test the hypothesis that a markedly reduced level of viral replication will limit the switch from M-tropic to T-tropic HIV-1 infection. We propose to block early stages, (prior to the synthesis of viral antigens), of HIV-1 infection by exploiting the properties of a recently discovered cellular inhibitor of HIV-1 gene trans-activation. This is significant since currently available immune therapies or the antiviral agents mainly target infected cells which display viral antigens. In spite of the progress in antiviral triple drug therapy, reservoirs of virus persist in lymph nodes that remain unaffected by currently available drugs (2-5, 7, 8, 15). We suggest that an endogenous inhibitor of early viral life cycle will complement the potency of available antiviral therapy to achieve a stable cure for AIDS. Importantly, the proposal is relevant to the goals of PA-98-040, since the inhibitory properties of the endogenous HIV-1 suppressor, NF90, is regulated by the mitogenic signal transduction pathways of human primary immune cells. A better understanding of the cell cycle, regulated control of HIV-I expression in human primary T-cells will be important to design stable cure for AIDS. The overall goal of this project is to build upon our preliminary studies and utilizing immunoliposomes targeted to CCR5 expressing cells, deliver the NF90 expression constructs to assess its effectiveness as an inhibitor of HIV-I replication in primary human lymphocytes.
