Targeting HIV transcription: the quest for a functional cure

Abstract

Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4(+)T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA's stem-bulge-loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P-TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P-TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers.

Fig. 1

HIV-1 transcription elongation. 1 Upon Tat acetylation on Lys28 by PCAF, 2 Tat recruits P-TEFb (CDK9/cyclin T1) from a large inactive complex with 7SK snRNA/MePCE/LARP7/HEXIM1. 3 Tat/P-TEFb complex binds to TAR. CDK9 phosphorylates Ser2 of the RNAPII CTD, stalled shortly after transcription initiation. 4 CDK9 phosphorylates the negative elongation factor NELF, which is released from RNAPII, and DSIF that becomes a positive transcription elongation factor. 5 Tat is acetylated at Lys50 by p300/CBP, resulting in the release of the Tat/P-TEFb complex from TAR. p300/CBP acetylates Nuc0 and Nuc1 allowing for chromatin remodeling. 6 Tat recruits to the initiation start site SWI/SNF, PCAF, and additional factors not depicted here to further promote transcription. Green arrow acetylation; red arrow phosphorylation

Fig. 2

Hypothetically, a transcription inhibitor could promote deep-latency and block reactivation. High levels of circulating virus are observed in the blood of infected individuals upon HIV infection. Upon ART initiation, viral mRNA is reduced to below 50 copies/ml and memory CD4⁺T cells remain latently infected. If ART is halted, there is an immediate rebound of virus production that correlates with CD4⁺T-cell reactivation. Combining a transcription inhibitor to ART could induce a state of deep-latency that would lead to the reduction in size of the viral reservoir

Fig. 3

Structure of selected HIV transcription inhibitors. Brackets target of the compound

Fig. 4

Multiple targets of a Tat inhibitor. The primary role of a Tat inhibitor is to block HIV transcription to promote a state of deep-latency and inhibit HIV reactivation. A Tat inhibitor might also reduce uptake of extracellular Tat by blocking its interaction with cellular receptors. Finally, a Tat inhibitor might impact the effect of extracellular Tat in the induction of pathways resulting in HAND or Kaposi’s sarcoma