TAT P59W

HIV-1 encodes for the small basic protein Tat (86-101 residues) that drastically enhances the efficiency of viral transcription. The mechanism enabling Tat nuclear import is not yet clear, but studies using reporter proteins fused to the Tat basic domain indicate that Tat could reach the nucleus by passive diffusion. Tat also uses an unusual transcellular transport pathway. The first step of this pathway involves high-affinity binding of Tat to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P(2)), a phospholipid that is concentrated in the inner leaflet of the plasma membrane and enables Tat recruitment at this level. Tat then crosses the plasma membrane to reach the outside medium. Although unconventional, Tat secretion by infected cells is highly active, and export is the major destination for HIV-1 Tat. Secreted Tat can bind to a variety of cell types using several different receptors. Most of them will allow Tat endocytosis. Upon internalization, low endosomal pH triggers a conformational change in Tat that results in membrane insertion. Later steps of Tat translocation to the target-cell cytosol are assisted by Hsp90, a general cytosolic chaperone. Cytosolic Tat can trigger various cell responses. Indeed, accumulating evidence suggests that extracellular Tat acts as a viral toxin that affects the biological activity of different cell types and has a key role in acquired immune-deficiency syndrome development. This review focuses on some of the recently identified molecular details underlying the unusual transcellular transport pathway used by Tat, such as the role of the single Trp in Tat for its membrane insertion and translocation.

The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable in the blood, with the aim of allowing patients to live without cART. Tat, the viral transactivator of transcription protein, plays a critical role in controlling HIV transcription, latency, and viral rebound following the interruption of cART treatment. Therefore, a logical approach for controlling HIV would be to block Tat. Tackling Tat with inhibitors has been a difficult task, but some recent discoveries hold promise. Two anti-HIV proteins, Nullbasic (a mutant of Tat) and HT1 (a fusion of HEXIM1 and Tat functional domains) inhibit viral transcription by interfering with the interaction of Tat and cellular factors. Two small molecules, didehydro-cortistatin A (dCA) and triptolide, inhibit Tat by different mechanisms: dCA through direct binding and triptolide through enhanced proteasomal degradation. Finally, two Tat-based vaccines under development elicit Tat-neutralizing antibodies. These vaccines have increased the levels of CD4+ cells and reduced viral loads in HIV-infected people, suggesting that the new vaccines are therapeutic. This review summarizes recent developments of anti-Tat agents and how they could contribute to a functional cure for HIV.

Over the past decades, much have been learned about HIV-1 virus and its molecular strategies for pathogenesis. However, HIV-1 still remains an enigmatic virus, particularly because of its unique proteins. Establishment of latency and reactivation is still a puzzling question and various temporal and spatial dynamics between HIV-1 proteins itself have given us new way of thinking about its pathogenesis. HIV-1 replication depends on Tat which is a small unstructured protein and subjected to various post-translational modifications for its myriad of functions. HIV-1 Tat protein modulates the functions of various strategic cellular pathways like proteasomal machinery and inflammatory pathways to aid in HIV-1 pathogenesis. Many of the recent findings have shown that Tat is associated with exosomes, cleared from HIV-1 infected cells through its degradation by diverse routes ranging from lysosomal to proteasomal pathways. HIV-1 Tat was also found to be associated with other HIV-1 proteins including Vpr, Nef, Nucleocapsid (NC) and Rev. Interaction of Tat with Vpr and Nef increases its transactivation function, whereas, interaction of Tat with NC or Rev leads to Tat protein degradation and hence suppression of Tat functions. Research in the recent years has established that Tat is not only important for HIV-1 promoter transactivation and virus replication but also modulating multiple cellular and molecular functions leading to HIV-1 pathogenicity. In this review we discussed various transcriptional and non-transcriptional HIV-1 Tat functions which modulate host cell metabolism during HIV-1 pathogenesis.