Epigenetic crosstalk in chronic infection with HIV-1

Lange, Ulrike; Verdikt, Roxane; Aït-Ammar, Amina; Lint, Carine Van

doi:10.1007/s00281-020-00783-3

Cited by 27 publications

(29 citation statements)

References 149 publications

(223 reference statements)

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“…Currently, no antiretroviral drugs inhibit basal transcription of provirus and blocks reactivation upon therapy (ART) interruption. It has been suggested that epigenetic silencing will be an important pre-requisite for persistent latency (81,82). Our expression and ChIP-qPCR data suggest that H2S could exert its influence on HIV replication machinery via activating YY1-an epigenetic silencer of HIV-1 LTR (56,68).…”

Section: Discussionmentioning

confidence: 66%

Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis

Pal

Agrawal

Rakshit

et al. 2021

Preprint

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A fundamental challenge in HIV eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral treatment (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H2S) in HIV latency and reactivation. We show that reactivation of HIV-1 is associated with down-regulation of the key H2S producing enzyme cystathionine-g-lyase (CTH) and reduction in endogenous H2S. Genetic silencing of CTH disrupts redox homeostasis, impairs mitochondrial function, and remodels the transcriptome of latent cells to trigger HIV reactivation. Chemical complementation of CTH activity using a slow-releasing H2S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-kB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4+ T cells from ART-suppressed human subjects, GYY4137 in combination with ART prevented viral rebound and improved mitochondrial bioenergetics. Moreover, prolonged exposure to GYY4137 exhibited no adverse influence on proviral content or CD4+ T cell subsets, indicating that diminished viral rebound is due to a loss of transcription rather than a selective loss of infected cells. In summary, this work provides mechanistic insight into H2S-mediated suppression of viral rebound and suggests the inclusion of an H2S donor in the current ART regimen to achieve a functional HIV-1 cure.

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Section: Discussionmentioning

confidence: 66%

Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis

Pal

Agrawal

Rakshit

et al. 2021

Preprint

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“…With an exciting recent work showing that viral cell-to-cell transmission primes T cells to latent HIV-1 infections [ 169 ], another important challenge will be to determine how the repressive epigenetic status of the HIV-1 promoter is established in the early stages of the infection. This will provide further insights into the interplay between the epigenetic control of the virus and epigenetic alterations in the host, which might have fundamental consequences for HIV-1 clinical management [ 170 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Mechanisms of HIV-1 Persistence

2021

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Eradicating HIV-1 in infected individuals will not be possible without addressing the persistence of the virus in its multiple reservoirs. In this context, the molecular characterization of HIV-1 persistence is key for the development of rationalized therapeutic interventions. HIV-1 gene expression relies on the redundant and cooperative recruitment of cellular epigenetic machineries to cis-regulatory proviral regions. Furthermore, the complex repertoire of HIV-1 repression mechanisms varies depending on the nature of the viral reservoir, although, so far, few studies have addressed the specific regulatory mechanisms of HIV-1 persistence in other reservoirs than the well-studied latently infected CD4+ T cells. Here, we present an exhaustive and updated picture of the heterochromatinization of the HIV-1 promoter in its different reservoirs. We highlight the complexity, heterogeneity and dynamics of the epigenetic mechanisms of HIV-1 persistence, while discussing the importance of further understanding HIV-1 gene regulation for the rational design of novel HIV-1 cure strategies.

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“…A role in the maintenance of viral latency was also reported for a genome-length antisense transcript devoid of poly-A tail (Transcript IV; Figure 3 ), which was detected in two chronically infected T-cell lines ( Saayman et al, 2014 ). In these cells, Transcript IV behaved as a long non-coding (lnc) RNA by recruiting chromatin modifying enzymes, such as DNA methyltransferase 3a (DNMT3a), Enhancer of Zeste Homolog 2 (EZH2), and Histone Deacetylase (HDAC)-1, to the 5' LTR of the provirus ( Saayman et al, 2014 ; Lange et al, 2020 ). This multiplicity of antisense transcripts characterized in vitro may be explained by the use of different methodological approaches in different studies.…”

Section: The Antisense Transcriptional Activity Of Hiv-1mentioning

confidence: 99%

Antisense Transcripts and Antisense Protein: A New Perspective on Human Immunodeficiency Virus Type 1

et al. 2021

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It was first predicted in 1988 that there may be an Open Reading Frame (ORF) on the negative strand of the Human Immunodeficiency Virus type 1 (HIV-1) genome that could encode a protein named AntiSense Protein (ASP). In spite of some controversy, reports began to emerge some years later describing the detection of HIV-1 antisense transcripts, the presence of ASP in transfected and infected cells, and the existence of an immune response targeting ASP. Recently, it was established that the asp gene is exclusively conserved within the pandemic group M of HIV-1. In this review, we summarize the latest findings on HIV-1 antisense transcripts and ASP, and we discuss their potential functions in HIV-1 infection together with the role played by antisense transcripts and ASPs in some other viruses. Finally, we suggest pathways raised by the study of antisense transcripts and ASPs that may warrant exploration in the future.

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Epigenetic crosstalk in chronic infection with HIV-1

Cited by 27 publications

References 149 publications

Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis

Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis

Epigenetic Mechanisms of HIV-1 Persistence

Antisense Transcripts and Antisense Protein: A New Perspective on Human Immunodeficiency Virus Type 1

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