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Review
. 2023 Dec 15;15(12):2435.
doi: 10.3390/v15122435.

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Natasha N Duggan  1 , Tatjana Dragic  1 , Sumit K Chanda  1 , Lars Pache  2
Affiliations
Review

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Natasha N Duggan et al. Viruses. .

Abstract

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells ("block and lock") or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host ("shock and kill"). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir.

Keywords: HIV cure; LRA; block and lock; human immunodeficiency virus; latency reversal; shock and kill; viral latency.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular pathways targeted by LRAs. (A) Epigenetic modifiers: HDACi, which prevents histone deacetylation, and HMTi, which disrupts the deposition of repressive methylation marks, promote a relaxed chromatin structure, enhancing the accessibility of the viral promoter. BET proteins also impact the regulation of HIV-1 transcription. BRD4 competes with Tat for P-TEFb binding, thereby limiting Tat-mediated transcriptional activation. By displacing BRD4 from chromatin, BETi frees P-TEFb and enables its binding of Tat. (B) Pattern recognition receptor signaling: The stimulation of endosomal or cell surface TLRs leads to the activation of transcription factors NF-κB, AP-1, NFAT, and/or IRF family members. Since many TLRs are not expressed at significant levels in CD4+ T cells, TLR agonists identified as LRAs act mostly indirectly by inducing type I interferon production in plasmacytoid dendritic cells, which causes the downstream activation of CD4+ T cells and induces HIV-1 latency reversal. (C) Canonical NF-κB signaling: The recruitment of TAK1 by a range of transmembrane receptors, including TNFR, leads to activation of the IKK complex, the degradation of IκBα, and the translocation of the transcriptions factors RelA and p50 to the nucleus. This pathway can be activated by PKCa or by disulfiram to promote HIV-1 transcription. (D) Non-canonical NF-κB signaling is activated by a different set of receptors than the canonical pathway, including CD40 and LTβR. Non-canonical NF-κB signaling can be induced by Smac mimetics that antagonize cIAP proteins, leading to an accumulation of NIK, the cleavage of p100, and the translocation of the transcription factors RelB and p52 to the nucleus. Illustration created with BioRender.com.
See this image and copyright information in PMC

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References

    1. Archin N.M., Margolis D.M. Emerging strategies to deplete the HIV reservoir. Curr. Opin. Infect. Dis. 2014;27:29–35. doi: 10.1097/QCO.0000000000000026. - DOI - PMC - PubMed
    1. Zicari S., Sessa L., Cotugno N., Ruggiero A., Morrocchi E., Concato C., Rocca S., Zangari P., Manno E.C., Palma P. Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART. Viruses. 2019;11:200. doi: 10.3390/v11030200. - DOI - PMC - PubMed
    1. Cai C.W., Sereti I. Residual immune dysfunction under antiretroviral therapy. Semin. Immunol. 2021;51:101471. doi: 10.1016/j.smim.2021.101471. - DOI - PMC - PubMed
    1. Alshehri A.M. Metabolic syndrome and cardiovascular risk. J. Fam. Community Med. 2010;17:73–78. doi: 10.4103/1319-1683.71987. - DOI - PMC - PubMed
    1. Bosho D.D., Dube L., Mega T.A., Adare D.A., Tesfaye M.G., Eshetie T.C. Prevalence and predictors of metabolic syndrome among people living with human immunodeficiency virus (PLWHIV) Diabetol. Metab. Syndr. 2018;10:10. doi: 10.1186/s13098-018-0312-y. - DOI - PMC - PubMed