Cure and Long-Term Remission Strategies

Mori, Luisa; Valente, Susana T.

doi:10.1007/978-1-0716-1871-4_26

Cited by 6 publications

(5 citation statements)

References 292 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability of epigenetic factors to silence HIV-1, suggested that it might be possible to exploit these mechanisms to permanently silence HIV-1-the "Block and Lock" strategy for an HIV cure [159]. In a primary T cell model of HIV-1 latency, ATACseq studies have shown that chromatin accessibility of the proviral genome is significantly reduced when the provirus becomes latent, signifying the acquisition of physical and epigenetic barriers to viral gene expression [123].…”

Section: Chromatin Organization Of Proviral Hiv-1 and Its Epigenetic ...mentioning

confidence: 99%

The cell biology of HIV-1 latency and rebound

Mbonye,

Karn

2024

Retrovirology

View full text Add to dashboard Cite

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.

show abstract

Section: Chromatin Organization Of Proviral Hiv-1 and Its Epigenetic ...mentioning

confidence: 99%

The cell biology of HIV-1 latency and rebound

Mbonye,

Karn

2024

Retrovirology

View full text Add to dashboard Cite

show abstract

“…The viral promoter, the 5′-long terminal repeat (5′-LTR), irrespective of the host integration site, displays a typical nucleosomal (Nuc) organization with Nuc-0 and Nuc-1 framing the transcription start site (TSS). The 5′-LTR contains multiple binding sites for host transcription factors that help regulate transcription [11,12]. The general mechanism (Fig.…”

Section: Hiv-1 Transcription and Latency Regulationmentioning

confidence: 99%

“…We review recent findings on HIV-1 transcriptional regulation, latency, and current HIV cure strategies hinging on HIV transcriptional modulation. [11,12]. The general mechanism (Fig.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

Gibaut

Mori

Valente

2023

Current Opinion in HIV and AIDS

Self Cite

View full text Add to dashboard Cite

Purpose of review This review highlights advances in HIV transcription and epigenetic latency mechanisms and outlines current therapeutic approaches to eliminate or block the HIV-1 latent reservoir. Recent findings Novel host factors have been reported to modulate HIV-1 transcription and latency. Chromatin affinity purification strategies followed by mass spectrometry (ChAP-MS) identified the chaperone protein p32 to play an important role in HIV-1 transcriptional regulation via interactions with the viral transcriptional activator Tat. Similarly, an shRNA screen identified the methyltransferase SMYD5 contributing to HIV-1 transcriptional activation also by modulating Tat activity. These new factors, among others, represent potential druggable targets that could be explored in the ‘block-and-lock’ or ‘shock-and-kill’ approaches. Summary The HIV-1 latent reservoir is established early after infection, persists during antiretroviral therapy, and is the source of viral rebound after treatment interruption. An HIV cure requires either eliminating this reservoir or blocking latent proviral reactivation in the absence of antiretroviral therapy (ART). Understanding the mechanisms and key-players modulating HIV transcriptional and reactivation may facilitate therapeutic advancements. Here we summarize, the latest findings on host factors’ roles in HIV transcriptional regulation.

show abstract

“…Some of the improved methods to flush the virus out of infected cells are latency reactivation-based, followed by killing HIV + immune cells to eradicate HIV reservoirs, i.e., “kick and kill”. Others suggest the “block and lock” approach for a functional cure of HIV 43 , 44 to prevent the production of new viruses after treatment interruption. 40 , 43 , 45 The “kick and kill” approach has been tested in several animal models of HIV latency and small clinical trials in PWH on suppressive ART.…”

Section: Hiv Transcription Integrated Stress Response and Hiv Latencymentioning

confidence: 99%

The integrated stress response signaling during the persistent HIV infection

Mendes,

Tang,

Jiang

2023

iScience

View full text Add to dashboard Cite

Cure and Long-Term Remission Strategies

Cited by 6 publications

References 292 publications

The cell biology of HIV-1 latency and rebound

The cell biology of HIV-1 latency and rebound

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

The integrated stress response signaling during the persistent HIV infection

Contact Info

Product

Resources

About