Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence

J Exp Med. 2021 Dec 6;218(12):e20211427. doi: 10.1084/jem.20211427. Epub 2021 Oct 12.


Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain-containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.

Publication types

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

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology*
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV-1 / genetics
  • HIV-1 / pathogenicity
  • HIV-1 / physiology*
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Male
  • Middle Aged
  • Proviruses / genetics
  • Virus Integration / physiology
  • Virus Latency


  • Anti-HIV Agents
  • Kruppel-Like Transcription Factors