New insights into transcription elongation control of HIV-1 latency and rebound. Issue 1 (January 2023)

• Record Type: Journal Article
• Authors: Mbonye, Uri; Kizito, Fredrick; Karn, Jonathan
• Is Part Of: Trends in immunology. Volume 44:Issue 1(2023)
• Page Start: 60
• Page End: 71
• Publication Date: 2023-01
• Subjects: HIV-1 latency -- HIV-1 reservoir -- latency reversal -- T cell receptor signaling -- P-TEFb -- HIV-1 Tat -- 7SK snRNP; Immunology -- Periodicals; 571.96
• DOI: 10.1016/j.it.2022.11.003
• Languages: English
• ISSNs: 1471-4906

Abstract

Highlights: HIV-1 latency can only be reversed in a minor fraction of human CD4 + T cells harboring genetically intact proviruses, posing a major hurdle to the elimination of the persistent reservoir. Although heterogeneous clones of latently infected cells that constitute the HIV-1 reservoir exist in a dynamic pseudo-steady state, a functional cure might be achieved by specifically targeting inducible subsets that serve as potential sources of viral rebound. Host and viral control of the transcription elongation factor P-TEFb (positive transcription elongation factor b) is a crucial rate-limiting step in the emergence of HIV-1 from latency. Therefore, comprehensively understanding its regulatory mechanisms in primary CD4 + T cells can lead to the design of more effective latency reversal agents. Sequestration of P-TEFb by 7SK snRNP (small nuclear ribonucleoprotein) is an essential feature of its regulation in primary CD4 + T cells. Both Tat and T cell signaling can remodel the ribonucleoprotein complex to facilitate the exchange of P-TEFb to proviral HIV-1. An optimal latency reversal strategy may entail HIV-1 promoter activation by either relieving epigenetic restrictions or through induction of noncanonical nuclear factor kappa B (NF-κB) signaling combined with a potent diacylglycerol mimic intended to stimulate RasGRP1-dependent biogenesis of transcriptionally active P-TEFb. Significance: Due to multiple cellular blocks in transcription, HIV-1 latency can only be reversed in a minor fraction of infected but potentially virus-producing CD4 + T cells from infected patients. Recent work shows that the biogenesis of the transcription elongation factor P-TEFb is a crucial rate-limiting step in the emergence of HIV-1 from latency. These new insights can help guide the design of more effective latency reversal agents as part of an HIV eradication strategy. Abstract: Antiretroviral therapy reduces circulating HIV-1 to undetectable amounts but does not eliminate the virus due to the persistence of a stable reservoir of latently infected cells. The reservoir is maintained both by proliferation of latently infected cells and by reseeding from reactivated cells. A major challenge for the field is to find safe and effective methods to eliminate this source of rebounding HIV-1. Studies on the molecular mechanisms leading to HIV-1 latency and reactivation are being transformed using latency models in primary and patient CD4 + T cells. These studies have revealed the central role played by the biogenesis of the transcription elongation factor P-TEFb (Positive Transcription Elongation Factor b) and its recruitment to proviral HIV-1, for the maintenance of viral latency and the control of viral reactivation.