A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

ABSTRACT: During HIV infection, a latent viral reservoir is formed that persists during antiretroviral therapy (ART) and is maintained by a heritable state of transcriptional repression. Recent findings indicate that much of the reservoir originates from infections occurring in the weeks near the time of ART initiation, raising the important possibility that interventions during this period might prevent reservoir seeding and substantially reduce reservoir size. Based on this concept, we tested the ability of compounds that target epigenetic machinery to prevent the establishment of latent HIV infection in primary CD4 T cells. We identified class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention, an activity distinct from latency reversal. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression, even after HDACi withdrawal, and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to a striking change in the memory subset distribution indicating reprogramming of cell identity. Through knockout of individual HDACs and use of HDAC-selective inhibitors, we determined that HDAC1 and HDAC3 play crucial and distinct roles in proviral silencing initiation. Overall, this work indicates that a network of HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus. Epigenetic reprogramming by clinical targeting of HDACs during ART initiation may represent a novel way to prevent seeding of the HIV reservoir in vivo

ORGANISM(S): Homo sapiens

PROVIDER: GSE199946 | GEO | 2023/08/08

REPOSITORIES: GEO