Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques

Sarah J. Byrnes, Kathleen Busman-Sahay, Thomas A. Angelovich, Skyler Younger, Sol Taylor-Brill, Michael Nekorchuk, Stephen Bondoc, Rachel Dannay, Margaret Terry, Catherine R. Cochrane, Trisha A. Jenkins, Michael Roche, Claire Deleage, Steven E. Bosinger, Mirko Paiardini, Bruce J. Brew, Jacob D. Estes, Melissa J. Churchill

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.

Original languageEnglish (US)
Article numbere1011290
JournalPLoS pathogens
Volume19
Issue number3
DOIs
StatePublished - Mar 2023

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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