Abstract

Three decades of extensive work in the HIV field have revealed key viral and host cell factors controlling proviral transcription. Various models of transcriptional regulation have emerged based on the collective information from in vitro assays and work in both immortalized and primary cell-based models. Here, we provide a recount of the past and current literature, highlight key regulatory aspects, and further describe potential limitations of previous studies. We particularly delve into critical steps of HIV gene expression including the role of the integration site, nucleosome positioning and epigenomics, and the transition from initiation to pausing and pause release. We also discuss open questions in the field concerning the generality of previous regulatory models to the control of HIV transcription in patients under suppressive therapy, including the role of the heterogeneous integration landscape, clonal expansion, and bottlenecks to eradicate viral persistence. Finally, we propose that building upon previous discoveries and improved or yet-to-be discovered technologies will unravel molecular mechanisms of latency establishment and reactivation in a “new era”.

Highlights

  • Three decades of extensive work in the HIV field have revealed key viral and host cell factors controlling proviral transcription

  • Given the multiple routes of latency establishment and features influencing proviral transcription, namely immune cell state, integration landscape, and complex circuit architecture (Figure 1A,B), it has become difficult to ascertain their precise contribution to proviral fate

  • We propose that further studies uncoupling their influence on proviral transcription will unravel molecular mechanisms of latency establishment and reactivation, and allow the identification of novel host targets, which may guide strategies to eliminate the persistent yet inducible latent reservoir

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Summary

The Latent Reservoir in the Spotlight

The development of combination anti-retroviral therapy (ART), which targets several steps of the viral life cycle, decreased patient viral titers to below the limit of detection using contemporary methods [1,2]. Initial studies used PCR-based techniques but were later found to have largely overestimated the reservoir magnitude [8,9,10,11,12], as the majority of latently-infected cells in patients hold replication-incompetent proviruses This discovery indicated that defective genomes are not the source of the rebound virus upon ceasing ART, they can otherwise contribute to continued immune activation and exhaustion [10,13]. More recent assays, such as the quantitative viral outgrowth assay (QVOA), measure the latent reservoir by computing the number of latently-infected resting CD4+ T cells that produce replication-competent virus after in vitro stimulation typically with strong T-cell agonists [14,15]. It was further suggested that clonal expansion can be driven by cytokine and antigen stimulation without causing antiviral effects or inducing viral production, thereby giving key biological insights suggesting an additional challenge to reverse latency in the clinics [30]

Routes of Latency Establishment
Integration Site Effects on HIV Proviral Transcription and Fate
Conclusions and Future Directions
Phases of the HIV Transcriptional Program
HIV Proviral Transcriptional Regulation in Homeostatic Conditions
Cis-Elements in the HIV Proviral Genome
Transcription Factors Acting on cis-Elements in the HIV Proviral Genome
Pol II Pausing at the HIV Proviral Genome and Elongation Factors
HIV Proviral Nucleosome Positioning and Epigenomics
Chromatin-Remodeling Complexes and Associated Factors
Histone Chaperones and Chromatin Reassembly Factors
Proviral Genome DNA Methylation
Disease Relevance and Current Therapeutic Challenges
The Ephemeral Nature of Ideas and Considerations for Future Research
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