TY - JOUR
T1 - Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques
AU - Byrnes, Sarah J.
AU - Busman-Sahay, Kathleen
AU - Angelovich, Thomas A.
AU - Younger, Skyler
AU - Taylor-Brill, Sol
AU - Nekorchuk, Michael
AU - Bondoc, Stephen
AU - Dannay, Rachel
AU - Terry, Margaret
AU - Cochrane, Catherine R.
AU - Jenkins, Trisha A.
AU - Roche, Michael
AU - Deleage, Claire
AU - Bosinger, Steven E.
AU - Paiardini, Mirko
AU - Brew, Bruce J.
AU - Estes, Jacob D.
AU - Churchill, Melissa J.
N1 - Publisher Copyright:
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.ppat.1011290
DO - 10.1371/journal.ppat.1011290
M3 - Article
C2 - 36989320
AN - SCOPUS:85152164836
SN - 1553-7366
VL - 19
JO - PLoS pathogens
JF - PLoS pathogens
IS - 3
M1 - e1011290
ER -