Accessory roles of Tat in HIV-1 replication

HIV-1复制与T细胞激活密切相关，因此，HIV-1使用多种策略来操纵宿主细胞以增加病毒复制。虽然HIV-1Tat蛋白是病毒LTR转录延伸所必需的，但它也有影响宿主细胞功能的辅助作用。在这项提案中，我们将确定HIV-1Tat蛋白如何调节细胞环境，以增加宿主细胞对HIV-1复制的容许性。在这项建议中要检验的假设是，除了众所周知的对病毒LTR转录的影响外，TAT还通过与T细胞信号通路的相互作用增加HIV-1的复制。这些相互作用需要TAT的第二外显子，并导致转录因子如核因子-kappaB的活性增加。为了验证这一假设，我们将量化TAT外显子2对HIV-1复制的优势，确定外显子2提供的复制优势是否通过与T细胞激活途径的相互作用来调节，并确定TAT如何调节其与宿主细胞的相互作用。因此，这项建议的总体目标是确定可归因于TAT第二外显子的功能，并确定这些功能在HIV-1复制和发病中的作用。

HIV-1 replication is closely linked to T cell activation, and thus, HIV-1 uses a number of strategies to manipulate the host cell to increase virus replication. While the HIV-1 Tat protein is essential for transcription elongation form the viral LTR, it also has accessory roles that affect host cell functions. In this proposal, we will determine how the HIV-1 Tat protein modulates the cellular environment to increase the permissiveness of the host cell to HIV-1 replication. The hypothesis to be tested in this proposal is that in addition to its well-known effects on transcription of the viral LTR, Tat increases HIV-1 replication through interaction with T cell signaling pathways. These interactions require the second exon of Tat and result in increased activity of transcription factors such as NF-kappaB. To test this hypothesis we will quantify the advantage to HIV-1 replication provided by exon 2 of Tat, determine if the replication advantage provided by exon 2 is mediated through interaction with T cell activation pathways, and determine how Tat mediates its interactions with the host cell. Thus, the overall goal of this proposal is to identify functions attributable to the second exon of Tat and to ascertain the role of these Tat functions in HIV-1 replication and pathogenesis.