HIV-1 Tat and Viral Latency: What We Can Learn from Naturally Occurring Sequence Variations

Abstract

Despite the effective use of antiretroviral therapy, the remainder of a latently HIV-1-infected reservoir mainly in the resting memory CD4+ T lymphocyte subset has provided a great setback toward viral eradication. While host transcriptional silencing machinery is thought to play a dominant role in HIV-1 latency, HIV-1 protein such as Tat, may affect both the establishment and the reversal of latency. Indeed, mutational studies have demonstrated that insufficient Tat transactivation activity can result in impaired transcription of viral genes and the establishment of latency in cell culture experiments. Because Tat protein is one of highly variable proteins within HIV-1 proteome, it is conceivable that naturally occurring Tat mutations may differentially modulate Tat functions, thereby influencing the establishment and/or the reversal of viral latency in vivo. In this mini review, we summarize the recent findings of Tat naturally occurring polymorphisms associating with host immune responses and we highlight the implication of Tat sequence variations in relation to HIV latency.

Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription

“…Since HIV-1 Tat protein plays a key role in viral transcriptional elongation through the interaction with positive transcription elongation factor b (P-TEFb) complex, composed of cyclin T1 and cyclin-dependent kinase 9 (Kamori and Ueno, 2017), we first determined the effect of levosimendan on Tat protein level and Tat-P-TEFb protein interaction in Tat-expressing HeLa cells. Neither the Tat protein level nor the Tat-P-TEFb protein interaction was affected by the treatment of levosimedan (Figure 5A–B).…”

Barriers for HIV Cure: The Latent Reservoir

“…159,160 P-TEFb is a protein complex containing cyclin T1 and CDK9 kinase, which phosphorylates the carboxylterminal domain of the RNA Pol II recruited at the 5¢ LTR, enhancing in turn its transcription elongation activity. 159,161 However, most P-TEFb molecules are held catalytically inactive through their association with the 7SK small nuclear ribonucleoprotein (snRNP) complex. Tat promotes P-TEFb dissociation from 7SK, allowing P-TEFb to become catalytically active, hyperphosphorylate RNA Pol II, and release the transcriptional pause.…”

“…From this point on, and due to a positive feedback, a highly efficient Tat-dependent HIV-1 transcription phase begins by the mechanisms described above. 82,159,161,162,172 Additionally, Tat recruits chromatinremodeling factors, such as SWI/SNF, which facilitate transcription by promoting DNA relaxation and consequently nuc-1 remodeling. 173 Tat's role in latency has been extensively documented.…”

“…173 Tat's role in latency has been extensively documented. 159,174 For instance, Tat protein alone was found to be sufficient to successfully reactivate HIV-1 transcription in latently infected CD4 + T cells isolated from patients undergoing cART. 159,175,176 This was demonstrated by delivering tat either by transduction with non-HIV vectors, 176 or by ectopically delivering recombinant Tat protein to these cells.…”

“…159,174 For instance, Tat protein alone was found to be sufficient to successfully reactivate HIV-1 transcription in latently infected CD4 + T cells isolated from patients undergoing cART. 159,175,176 This was demonstrated by delivering tat either by transduction with non-HIV vectors, 176 or by ectopically delivering recombinant Tat protein to these cells. 175 In this particular case, a soluble Tat-GFP chimeric protein was produced from pancreatic cells of transgenic mice, and delivered to primary, latently infected CD4 + T cells of patients undergoing cART.…”