Early colorectal responses to hiv-1 and modulation by antiretroviral drugs

Carolina Herrera*, Mike D. McRaven, Ken G. Laing, Jayne Dennis, Thomas J. Hope, Robin J. Shattock

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Innate responses during acute HIV infection correlate with disease progression and patho-genesis. However, limited information is available about the events occurring during the first hours of infection in the mucosal sites of transmission. With an ex vivo HIV-1 challenge model of human colorectal tissue we assessed the mucosal responses induced by R5-and X4-tropic HIV-1 isolates in the first 24 h of exposure. Microscopy studies demonstrated virus penetration of up to 39 µm into the lamina propia within 6 h of inoculation. A rapid, 6 h post-challenge, increase in the level of secretion of inflammatory cytokines, chemokines, interferon-γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) was observed following exposure to R5-or X4-tropic isolates. This profile persisted at the later time point measured of 24 h. However, exposure to the X4-tropic isolate tested induced greater changes at the proteomic and transcriptomic levels than the R5-tropic. The X4-isolate induced greater levels of CCR5 ligands (RANTES, MIP-1α and MIP-1β) secretion than R5-HIV-1. Potential drugs candidates for colorectal microbicides, including entry, fusion or reverse transcriptase inhibitors demonstrated differential capacity to modulate these responses. Our findings indicate that in colorectal tissue, inflammatory responses and a Th1 cytokine profile are induced in the first 24 h following viral exposure.

Original languageEnglish (US)
Article number231
JournalVaccines
Volume9
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Antiretrovirals
  • HIV-1
  • Mucosal tissue
  • Pre-exposure prophylaxis

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Drug Discovery
  • Infectious Diseases
  • Pharmacology (medical)

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