HIV, SIV, and related lentiviruses of other species are unusual in that their envelope glycoproteins have very long cytoplasmic domains (CD);however, investigation of the functional contributions of the unusually long CDs has received little attention. The proposed studies will build upon a recent discovery made by the Desrosiers laboratory, that the cytoplasmic domains of gp41 (gp41CD) of both HIV-1 and SIV induce robust activation of the transcription factor NF-?B. Binding studies further revealed that gp41CD of HIV-1, but not SIV, interacts specifically and efficiently with TGF-?-activated Kinase 1 (TAK1), a key regulator of NF-?B signaling. Replication studies with wild-type HIV-1 and a mutant virus deficient in the ability to activate NF-?B demonstrated that NF-?B activation by gp41CD is important for the virus'ability to replicate in non- or minimally-activated CD4+ T-lymphocytes. These findings demonstrated a novel, evolutionarily conserved role for gp41CD in activating the NF-?B transcription factor. The proposed studies are directed toward investigating in precise detail how the cytoplasmic domains of gp41 (gp41CD) of HIV-1 and SIV lead to activation of NF-?B. Biochemical, genetic, and structural studies will focus on defining the signaling events, cellular interaction partners, and molecular mechanisms of gp41CD-induced NF-?B activation for promoting viral replication (Aim 1). Our studies will further determine the physiologic relevance of gp41CD-induced NF-?B activation for SIV replication and pathogenesis in vivo (Aim 2). Taken together, these studies will not only greatly expand our understanding of the modulation of key signaling pathways by HIV/SIV gp41, but may also define new therapeutic targets for the treatment of HIV infection in humans.
The proposed study will delineate the molecular mechanisms by which the cytoplasmic domains of HIV and SIV gp41 activate NF-kB to promote virus replication. Furthermore, this study will determine the physiologic relevance of gp41-mediated NF-kB activation for SIV replication and pathogenicity in vivo. These studies will provide detailed insights into a newly-discovered strategy used by HIV/SIV to facilitate its own replication, which may ultimately contribute to the establishment of new therapeutic strategies for HIV infection.