Structural and functional insights into IκB-α/HIV-1 Tat interaction.

Protein-protein interactions play fundamental roles in physiological and pathological biological processes. The characterization of the structural determinants of protein-protein recognition represents an important step for the development of molecular entities able to modulate these interactions. We have recently found that IκB-α (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) blocks the HIV-1 expression and replication in a NF-κB-independent manner by directly binding to the virus-encoded Tat transactivator.

IkappaB-alpha represses the transcriptional activity of the HIV-1 Tat transactivator by promoting its nuclear export.

The long terminal repeat of human immunodeficiency virus, type 1 (HIV-1) contains an NF-kappaB enhancer and is potently inhibited by IkappaB-alphaS32/36A, a proteolysis-resistant inhibitor of NF-kappaB transacting factors. The evidence that NF-kappaB is dispensable for HIV-1 expression raises the question of whether IkappaB-alpha represses the HIV-1 transcription by mechanisms distinct from NF-kappaB inhibition. Here, we report that IkappaB-alpha negatively regulates the HIV-1 expression and replication in an NF-kappaB-independent manner by directly binding to Tat, which results in the nuclear export and cytoplasmic sequestration of the viral transactivator.

Inhibition of HIV-1 replication in primary human monocytes by the IkappaB-alphaS32/36A repressor of NF-kappaB.

Background: The identification of the molecular mechanisms of human immunodeficiency virus type 1, HIV-1, transcriptional regulation is required to develop novel inhibitors of viral replication. NF-kappaB transacting factors strongly enhance the HIV/SIV expression in both epithelial and lymphoid cells. Controversial results have been reported on the requirement of NF-kappaB factors in distinct cell reservoirs, such as CD4-positive T lymphocytes and monocytes.

High attenuation and immunogenicity of a simian immunodeficiency virus expressing a proteolysis-resistant inhibitor of NF-kappaB.

NF-kappaB/IkappaB proteins play a major role in the transcriptional regulation of human immunodeficiency virus, type-1 (HIV-1). In the case of simian immunodeficiency virus (SIV) the cellular factors required for the viral transcriptional activation and replication in vivo remain undefined. Here, we demonstrate that the p50/p65 NF-kappaB transcription factors enhanced the Tat-mediated transcriptional activation of SIVmac239.

Physical and functional interaction of HIV-1 Tat with E2F-4, a transcriptional regulator of mammalian cell cycle.

Tat protein of the human immunodeficiency virus type-1 (HIV-1) plays a critical role in the regulation of viral transcription and replication. In addition, Tat regulates the expression of a variety of cellular genes and could account for AIDS-associated diseases including Kaposi's Sarcoma and non-Hodgkin's lymphoma by interfering with cellular processes such as proliferation, differentiation, and apoptosis. The molecular mechanisms underlying the pleiotropic activities of Tat may include the generation of functional heterodimers of Tat with cellular proteins.