Apobec3A maintains HIV-1 latency through recruitment of epigenetic silencing machinery to the long terminal repeat

Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2282-2289. doi: 10.1073/pnas.1819386116. Epub 2019 Jan 22.

Abstract

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated "A3A") in maintaining the latency state within HIV-1-infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5' long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

Keywords: T cells; TRIM28; epigenetic regulation; reactivation; viral latency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Cytidine Deaminase / chemistry
  • Cytidine Deaminase / metabolism*
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Viral
  • Gene Silencing*
  • HIV Infections / metabolism*
  • HIV Infections / virology*
  • HIV Long Terminal Repeat*
  • HIV-1 / physiology*
  • Humans
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteins / chemistry
  • Proteins / metabolism*
  • Sequence Deletion
  • Sp1 Transcription Factor / metabolism
  • Virus Activation / genetics
  • Virus Latency*

Substances

  • NF-kappa B
  • Proteins
  • Sp1 Transcription Factor
  • APOBEC3A protein, human
  • Cytidine Deaminase