Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents

AIDS. 2020 Nov 15;34(14):2013-2024. doi: 10.1097/QAD.0000000000002684.


Objective: While latently HIV-infected cells have been described in the blood, it is unclear whether a similar inducible reservoir exists in the gut, where most HIV-infected cells reside. Tissue-specific environments may contribute to differences in the mechanisms that govern latent HIV infection and amenability to reactivation. We sought to determine whether HIV-infected cells from the blood and gut differ in their responses to T-cell activation and mechanistically distinct latency reversing agents (LRAs).

Design: Cross sectional study using samples from HIV-infected individuals (n = 11).

Methods: Matched peripheral blood mononuclear cells (PBMC) and dissociated total cells from rectum ± ileum were treated ex vivo for 24 h with anti-CD3/CD28 or LRAs in the presence of antiretrovirals. HIV DNA and 'read-through', initiated, 5' elongated, completed, and multiply-spliced HIV transcripts were quantified using droplet digital PCR.

Results: T-cell activation increased levels of all HIV transcripts in PBMC and gut cells, and was the only treatment that increased multiply-spliced HIV RNA. Disulfiram increased initiated HIV transcripts in PBMC but not gut cells, while ingenol mebutate increased HIV transcription more in gut cells. Romidepsin increased HIV transcription in PBMC and gut cells, but the increase in transcription initiation was greater in PBMC.

Conclusion: The gut harbors HIV-infected cells in a latent-like state that can be reversed by T-cell activation involving CD3/CD28 signaling. Histone deacetylation and protein kinase B may contribute less to HIV transcriptional initiation in the gut, whereas protein kinase C may contribute more. New LRAs or combinations are needed to induce multiply-spliced HIV and should be tested on both blood and gut.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes
  • Cross-Sectional Studies
  • Diterpenes
  • Gastrointestinal Microbiome*
  • HIV Infections / blood*
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV-1 / genetics*
  • HIV-1 / physiology*
  • Humans
  • Leukocytes, Mononuclear
  • Polymerase Chain Reaction
  • RNA, Viral
  • Virus Activation / genetics
  • Virus Latency / physiology*


  • 3-ingenyl angelate
  • Diterpenes
  • RNA, Viral