Control of acute HIV-1 infection: Intracellular immunization with Herpesvirus saimiri transforming proteins, Tip and StpC and the effect of opiate abuse

T-lymphocytes transformed by Herpesvirus saimiri (HVS) become more permissive to replication of M- and T-tropic human immunodeficiency virus type 1 (HIV-1). Two open reading frames tyrosine-kinase interacting protein (Tip) and saimiri transformation-associated protein subgroup C(StpC), which are unique to HVS, are necessary for HVS induced T-cell transformation and are candidates for conferring the permissive phenotype to T cells. Replication, of X4 strains of HIV-1 measured by Tat protein levels, syncytia formation, and reverse transcription activity, was restricted in Tip-expressing T-cells while enhanced in T-cells expressing StpC demonstrating control of X4 strains replication. However, it was unknown whether independent expression of Tip or StPC expression could also regulate replication of R5 strains and dual tropic strains of HIV-1. In this study, we investigated the effects of Tip- and/or StpC expression on replication of R5 strains of HIV-1 in both T-cell lines and primary lymphocytes. We show that Tip and StpC modulate the replication of R5 as well as dual tropic strains of HIV-1 in a manner similar to that observed for X4 strains of HIV-1.{09}Replication of R5 strains of HIV-1 in T cells and primary cells was restricted by Tip while StpC up-regulated viral production compared to T-cells transduced with the empty vector alone.; Understanding pathways whereby Tip and StpC alter HIV-1 replication may uncover novel therapeutic approaches to HIV-1 infection. Here we provide evidence indicating that Tip-mediated restriction of HIV-1 replication is bi-modal - partly based on Lek independent inhibition Tat trans-activation of HIV-1 long terminal repeat (LTR) and on Lck-dependent restriction of the release of infectious HIV-1. In addition, T-cells transiently transfected with Tip exhibit increased activation of Stats 1 and 3, enhanced expression of PKR/p68, and induction of an intracellular IFN-gamma-like anti-viral state. Taken together, these studies show that Tip disrupts HIV-1 compensatory mechanism(s) for enhanced viral transcription and pathogenicity.; We demonstrate that Nef interferes with Tip-associated inhibition of Tat-mediated transactivation of the LTR by synergizing with Tat to overcome the block. We provide evidence showing that not only does Tip inhibit Tat-mediated transactivation of the LTR, Tip also interferes with Nef by blocking Nef-Lck interactions in lipid rafts. As a consequence, Nef's ability to down regulate surface expression of CD4 on infected cells is impaired and the release of virus is restricted. (Abstract shortened by UMI.)...