Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration

Thierry, Sylvain; Benleulmi, Mohamed Salah; Sinzelle, Ludivine; Thierry, Eloïse; Calmels, Christina; Chaignepain, Stéphane; Waffo-Téguo, Pierre; Mérillon, Jean Michel; Budke, Brian; Pasquet, Jean‐Max; Litvak, Simón; Ciuffi, Angela; Sung, Patrick; Connell, Philip P.; Hauber, Ilona; Hauber, Joachim; Andréola, Marie Line; Delelis, Olivier; Parissi, Vincent

doi:10.1016/j.chembiol.2015.04.020

Cited by 10 publications

(11 citation statements)

References 31 publications

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“…Consistent with this, resveratrol inhibits HIV-1 expression in a HeLa cell line containing an integrated HIV-1 promoter-reporter module via the activation of SIRT1 (25). The concentrations of resveratrol and pterostilbene used to achieve half-maximum inhibition of HIV-1 integration (78) and Tat transactivation (25) (47.5 M and 50 M, respectively) were up to 10 times higher than the concentration that we found completely inhibited HIV-1 in resting CD4 T cells (5 M). Indeed, Fontecave et al showed that 10 M resveratrol can completely destroy the catalytic tyrosyl radical in a biochemical assay (20), and this concentration closely matched the IC 90 of resveratrol in our model.…”

Section: Discussionmentioning

confidence: 53%

“…Resveratrol and, presumably, pterostilbene target cellular pathways other than the RNR pathway (3,4,(71)(72)(73)(74)(75)(76)(77). Pterostilbene can inhibit HIV-1 integrase in vitro and partially inhibit HIV-1 infection of a transformed fibroblastic cell line, 293T (19,78). Most prominent among the known resveratrol and pterostilbene targets is activation of Sirtuin 1 (SIRT1), an NAD ϩ -dependent deacetylase (79).…”

Section: Discussionmentioning

confidence: 99%

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Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene

Chan

Trinité

Levy

2017

Antimicrob Agents Chemother

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HIV-1 infection of resting CD4 T cells plays a crucial and numerically dominant role during virus transmission at mucosal sites and during subsequent acute replication and T cell depletion. Resveratrol and pterostilbene are plant stilbenoids associated with several health-promoting benefits. Resveratrol has been shown to inhibit the replication of several viruses, including herpes simplex viruses 1 and 2, papillomaviruses, severe acute respiratory syndrome virus, and influenza virus. Alone, resveratrol does not inhibit HIV-1 infection of activated T cells, but it does synergize with nucleoside reverse transcriptase inhibitors in these cells to inhibit reverse transcription. Here, we demonstrate that resveratrol and pterostilbene completely block HIV-1 infection at a low micromolar dose in resting CD4 T cells, primarily at the reverse transcription step. The anti-HIV effect was fully reversed by exogenous deoxynucleosides and Vpx, an HIV-1 and simian immunodeficiency virus protein that increases deoxynucleoside triphosphate (dNTP) levels. These findings are consistent with the reported ability of resveratrol to inhibit ribonucleotide reductase and to lower dNTP levels in cells. This study supports the potential use of resveratrol, pterostilbene, or related compounds as adjuvants in anti-HIV preexposure prophylaxis (PrEP) formulations.KEYWORDS resting CD4 T cells, human immunodeficiency virus, pterostilbene, resveratrol, reverse transcription, stilbenoid, PrEP T he stilbenoids resveratrol (RES) and pterostilbene (PTE) function as plant phytoalexins, i.e., defensive compounds generated in response to parasitic attack. Resveratrol is found in grape skins, small berries, peanuts, and some nuts and has been extensively studied as an active ingredient of red wine, contributing to the health benefits associated with the French paradox and other potential life-extending properties, including anti-inflammatory, anticancer, and antidiabetes activities (1). Pterostilbene is a natural dimethylated analog of resveratrol also found in grape skins, berries, peanuts, and almonds (2). Pterostilbene has anti-inflammatory activity (3, 4), is more lipophilic than resveratrol, and has greater stability in vitro and in vivo (5-8).Resveratrol inhibits the replication of several viruses, including herpes simplex viruses (HSVs) 1 and 2, varicella-zoster virus, papillomaviruses, and influenza virus (9-12). Topical application of resveratrol has been found to inhibit HSV vaginal transmission in mice, suggesting that it might be useful as a topical microbicide (13). Alone, resveratrol does not inhibit wild-type (WT) human immunodeficiency virus type 1 (HIV-1) replication in activated T cells or in transformed T cell lines (14, 15), but it does potentiate inhibition of reverse transcription by nucleoside analog reverse transcriptase (RT) inhibitors (NRTIs), including tenofovir (TFV), didanosine, zidovudine (AZT), and emtricitabine (FTC) (14,16). Resveratrol alone does, however, inhibit reverse transcription in NRTI-resistant RT muta...

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene

Chan

Trinité

Levy

2017

Antimicrob Agents Chemother

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“…The involvement of the base excision repair (BER) pathway was in part confirmed by biochemical and genetic studies [15–17]. RAD51 protein, which is an important player in HR, was found to affect HIV-1 integration [18, 19]. The involvement of the NHEJ pathway in HIV-1 replication has undergone particularly extensive studies providing numerous data showing that depletion of proteins involved in this pathway decreases HIV-1 infectivity [9, 20–25].…”

Section: Introductionmentioning

confidence: 99%

NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase

et al. 2019

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BackgroundHIV-1 integration results in genomic DNA gaps that are repaired by cellular DNA repair pathways. This step of the lentiviral life cycle remains poorly understood despite its crucial importance for successful replication. We and others reported that Ku70 protein of the non-homologous end joining pathway (NHEJ) directly binds HIV-1 integrase (IN). Here, we studied the importance of this interaction for post-integrational gap repair and the recruitment of NHEJ factors in this process.ResultsWe engineered HIV-based pseudovirus with mutant IN defective in Ku70 binding and generated heterozygous Ku70, Ku80 and DNA-PKcs human knockout (KO) cells using CRISPR/Cas9. KO of either of these proteins or inhibition of DNA-PKcs catalytic activity substantially decreased the infectivity of HIV-1 with native IN but not with the mutant one. We used a recently developed qPCR assay for the measurement of gap repair efficiency to show that HIV-1 with mutant IN was defective in DNA post-integrational repair, whereas the wild type virus displayed such a defect only when NHEJ system was disrupted in any way. This effect was present in CRISPR/Cas9 modified 293T cells, in Jurkat and CEM lymphoid lines and in primary human PBMCs.ConclusionsOur data provide evidence that IN recruits DNA-PK to the site of HIV-1 post-integrational repair due to Ku70 binding—a novel finding that explains the involvement of DNA-PK despite the absence of free double stranded DNA breaks. In addition, our data clearly indicate the importance of interactions between HIV-1 IN and Ku70 in HIV-1 replication at the post-integrational repair step.

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“…For the provirus to integrate, a double strand DNA break is required. HIV-1 integration is linked to RAD51 (Thierry et al, 2015), and through the viral Vpr protein, HIV-1 extensively engages several DNA damage response pathways (Li et al, 2020). Vpr plays a key role by inhibiting specific pathways of the DNA repair and also inducing cell cycle arrest and upregulating p21 (Vaźquez et al, 2005).…”

Section: Hiv-1 Interacts With Dna Damage Response Pathwaysmentioning

confidence: 99%

Targeting Epigenetics to Cure HIV-1: Lessons From (and for) Cancer Treatment

Svensson

2021

Front. Cell. Infect. Microbiol.

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The Human Immunodeficiency Virus type 1 (HIV-1) integrates in the host genome as a provirus resulting in a long-lived reservoir of infected CD4 cells. As a provirus, HIV-1 has several aspects in common with an oncogene. Both the HIV-1 provirus and oncogenes only cause disease when expressed. A successful cure of both cancer and HIV-1 includes elimination of all cells with potential to regenerate the disease. For over two decades, epigenetic drugs developed against cancer have been used in the HIV-1 field to modulate the state of the proviral chromatin. Cells with an intact HIV-1 provirus exist in three states of infection: productive, inducible latent, and non-inducible latent. Here focus is on HIV-1, transcription control and chromatin structure; how the inducible proviruses are maintained in a chromatin structure that allows reactivation of transcription; and how transcription switches between different stages to allow for an abundance of different transcripts from a single promoter. Recently it was shown that a functional cure of HIV can be achieved by encapsulating all intact HIV-1 proviruses in heterochromatin, giving hope that epigenetic interventions may be used to end the HIV-1 epidemic.

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Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration

Cited by 10 publications

References 31 publications

Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene

Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene

NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase

Targeting Epigenetics to Cure HIV-1: Lessons From (and for) Cancer Treatment

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