Accessory roles of Tat in HIV-1 replication

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

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.