biostudies-literaturePeterson JJNational Institute of Allergy and Infectious DiseasesNIDA NIH HHSNIAID NIH HHSNIEHS NIH HHSQura TherapeuticsNational Institutes of HealthNational Institute on Drug Abuse1617-1633.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC10754471biostudies-literatureUnknown30(12)A long-lived latent reservoir of HIV-1-infected CD4 T cells persists with antiretroviral therapy and prevents cure. We report that the emergence of latently infected primary CD4 T cells requires the activity of histone deacetylase enzymes HDAC1/2 and HDAC3. Data from targeted HDAC molecules, an HDAC3-directed PROTAC, and CRISPR-Cas9 knockout experiments converge on a model where either HDAC1/2 or HDAC3 targeting can prevent latency, whereas all three enzymes must be targeted to achieve latency reversal. Furthermore, HDACi treatment targets features of memory T cells that are linked to proviral latency and persistence. Latency prevention is associated with increased H3K9ac at the proviral LTR promoter region and decreased H3K9me3, suggesting that this epigenetic switch is a key proviral silCell chemical biologyA histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV-infected cells.PMC10754471P30 AI050410R01AI143381UM1 AI164567R33 DA047023T32AI007419T32 AI007419R33DA047023T32 ES007018UM1AI164567R01 AI143381R61 DA047023Peterson JJLewis CABurgos SDZou FRichardson BManickam AMargolis DMSimon JMBrowne EPGoonetilleke NClutton GXu YRowley AAfalseA histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV-infected cells.A long-lived latent reservoir of HIV-1-infected CD4 T cells persists with antiretroviral therapy and prevents cure. We report that the emergence of latently infected primary CD4 T cells requires the activity of histone deacetylase enzymes HDAC1/2 and HDAC3. Data from targeted HDAC molecules, an HDAC3-directed PROTAC, and CRISPR-Cas9 knockout experiments converge on a model where either HDAC1/2 or HDAC3 targeting can prevent latency, whereas all three enzymes must be targeted to achieve latency reversal. Furthermore, HDACi treatment targets features of memory T cells that are linked to proviral latency and persistence. Latency prevention is associated with increased H3K9ac at the proviral LTR promoter region and decreased H3K9me3, suggesting that this epigenetic switch is a key proviral sil2023-01-01T00:00:00Z2023 Dec2026-06-01T12:45:46.885Z2025-04-04T20:28:07.339ZS-EPMC107544713813488110.1016/j.chembiol.2023.11.009