Transcriptional Stochasticity as a Key Aspect of HIV-1 Latency

Damour, Alexia; Slaninova, Vera; Radulescu, Ovidiu; Bertrand, Edouard; Basyuk, Eugenia

doi:10.3390/v15091969

Cited by 7 publications

(3 citation statements)

References 145 publications

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“…However, advancement of modeling and analysis tools has revealed that the simple two-state model and associated parameters may not sufficiently recapitulate the complex relationship between these features. As such, more complex models incorporating some of these features such as RNAPII pausing and chromatin have been devised (reviewed in [ 124 ]). A common outcome of all these complex models is the realization that the HIV-1 transcriptional program is fragile and that perturbations at any of its regulatory phases: basal, host, and/or viral ( Figure 4 ) alters the magnitude of latent HIV-1 exit from latency, likely contributing to spontaneous reactivation (viral blips) [ 80 , 92 , 98 , 106 , 109 , 121 , 125 , 126 , 127 ].…”

Section: Discussion and Future Perspectivementioning

confidence: 99%

“…An outstanding question of several landmarks discoveries in the field, including the topic of stochasticity [ 124 ], is what selective pressures shaped the viral genome to be regulated in such a manner and what are the evolutionary advantages. This is extremely important, given that two distinct patterns of gene activation (synchronous and stochastic) have been proposed to regulate gene expression in Drosophila [ 130 ] and mammals (reviewed in [ 97 ]).…”

Section: Discussion and Future Perspectivementioning

confidence: 99%

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Mathematical Models of HIV-1 Dynamics, Transcription, and Latency

D’Orso,

Forst

2023

Viruses

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HIV-1 latency is a major barrier to curing infections with antiretroviral therapy and, consequently, to eliminating the disease globally. The establishment, maintenance, and potential clearance of latent infection are complex dynamic processes and can be best described with the help of mathematical models followed by experimental validation. Here, we review the use of viral dynamics models for HIV-1, with a focus on applications to the latent reservoir. Such models have been used to explain the multi-phasic decay of viral load during antiretroviral therapy, the early seeding of the latent reservoir during acute infection and the limited inflow during treatment, the dynamics of viral blips, and the phenomenon of post-treatment control. Finally, we discuss that mathematical models have been used to predict the efficacy of potential HIV-1 cure strategies, such as latency-reversing agents, early treatment initiation, or gene therapies, and to provide guidance for designing trials of these novel interventions.

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Section: Discussion and Future Perspectivementioning

confidence: 99%

Section: Discussion and Future Perspectivementioning

confidence: 99%

Mathematical Models of HIV-1 Dynamics, Transcription, and Latency

D’Orso,

Forst

2023

Viruses

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“…One important consequence of the promoter-proximal pausing at the HIV-1 LTR is that HIV transcription at the level of an individual provirus occurs in rapid bursts [309,310]. The stochastic switching of the viral promoter between ON and OFF states is caused by random binding dynamics of the core transcription factors TBP, Sp1, and NF-κB, which can lead to intermittent clearance of the paused RNAP II complexes [311].…”

Section: Stochastic Transcription From the Viral Ltrmentioning

confidence: 99%

The cell biology of HIV-1 latency and rebound

Mbonye,

Karn

2024

Retrovirology

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Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset of memory CD4+ T cells, pose the primary barrier to a cure for HIV-1 infection because they are the source of the viral rebound that almost inevitably follows the interruption of antiretroviral therapy. Over the last 30 years, many of the factors essential for initiating HIV-1 transcription have been identified in studies performed using transformed cell lines, such as the Jurkat T-cell model. However, as highlighted in this review, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. Furthermore, the central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells—the “Shock and Kill” strategy. For “Shock and Kill” to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs.

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