The HIV-1 Tat Protein: A Multifaceted Target for Novel Therapeutic Opportunities

Abstract

Transcription of the integrated HIV-1 proviral genome is an essential step in the retrovirus life cycle and thus an appealing target for chemotherapeutic intervention to restrict retroviral replication. A fundamental role in this process is exerted by the viral protein Tat, a powerful transactivator of viral gene expression. This protein binds a structured RNA sequence at the 5'-ends of all nascent viral mRNAs and promotes transcription by mediating the recruitment to the viral promoter of cellular factors required for chromatin remodelling and transcriptional processivity. In addition to these transcriptional activities, Tat is released from the cells and enters neighbouring cells when present in the extracellular environment, a process that is possibly involved in HIV disease pathogenesis. Given its pleiotropic functions, the protein represents a highly appealing target for drug development. Here I will summarise the known molecular mechanisms by which Tat exerts its activities and review the currently available compounds that interfere with the process of transcriptional activation of the HIV-1 provirus.

Developmental Regulators Containing the I-mfa Domain Interact with T cyclins and Tat and Modulate Transcription

“…Therefore the mechanism by which I-mfa and HIC inhibit transcription may involve recruitment of P-TEFb to the transcription complex rather than a direct effect on its kinase activity. Our studies with Tat truncations (Figure 5(d)) do not support the conclusion 10 that HIC binds to the Tat nuclear localization signal in its basic domain (aa [49][50][51][52][53][54][55][56][57]. Moreover, we did not observe relocalization of Tat to the cytoplasm in the presence of HIC.…”

“…Tat's interaction with TAR RNA is mediated via its arginine/lysine-rich basic domain. In addition to its major role in recruiting P-TEFb, Tat interacts with numerous cellular proteins to facilitate HIV-1 infection (for reviews see [52][53][54][55]. We and others have previously shown that HIC interacts with first exon Tat (aa 1-72) in vivo.…”

BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

“…Tat being originally discovered as the main transactivator of the viral genome, its inhibition has been initially approached by means of intracellular inhibitors (Giacca, 2004; Richter and Palù, 2006) aimed at the impairment of Tat nuclear translocation or of Tat/TAR interaction. More recently, when the biological relevance of extracellular Tat was assessed, a whole new set of extracellular inhibitors was developed (Rusnati and Presta, 2002b;.…”

The Regulation of HIV-1 mRNA Biogenesis

“…Nevertheless, several drugs inhibiting different aspects of Tat transactivation are currently being tested. Different classes of compounds have been shown to specifically inhibit viral transcription by: (i) binding the TAR sequence, (ii) binding Tat, (iii) inhibiting PTEF-b components and (iv) generally inhibiting transactivation by mechanisms not yet well defined (Giacca, 2004). Small molecules that inhibit the splicing activity of SR proteins have also been shown to efficiently repress viral replication in peripheral blood mononuclear cells (PBMC) with little cell toxicity (Bakkour, et al, 2007).…”