Sex difference in intestinal immune dysfunction, SHIV infection and reservoir

PROJECT SUMMARY
Gastrointestinal malfunctions and immune activation remain significant health issues for people living with
HIV/AIDS in the era of anti-retroviral therapy (ART). Immune activation fuels HIV reservoirs that are established
early during infection and support virus rebound after ART interruption (ATI). Increasing evidence points toward
sex differences in HIV pathogenesis, disease progression, and persistence. Identifying sex-specific immune
parameters associated with viral persistence and rebound will be critical to our long term goal of developing
personalized therapeutic strategies to reliably halt HIV-associated chronic diseases, and to target HIV reservoirs.
In subjects without ART, women have higher levels of immune activation than men and have a higher risk of
developing AIDS. Sex differences in immune activation in HIV-infected subjects on ART are less definitive,
possibly due to confounding factors, including gender (involving social/behavior factors) differences in seeking
treatment. Recent evidence identifying estrogen receptor 1 as a key regulator of HIV latency in CD4+ T cells
suggests the involvement of estrogen signaling in sex-based differences in HIV persistence. However, the role
of estrogen in HIV persistence in vivo remains unknown, as estrogen induces type I IFNs and other pro-
inflammatory cytokines, resulting in immune activation. Research in this area has been lacking a reliable animal
model. In that regard, we have developed a rhesus macaque (RM) model that mimics key features of human
HIV infection providing promising avenues for pursuing sex-based difference studies. The model, which employs
R5 SHIV C109 intrarectal challenge, displays a spectrum of disease outcomes similar to human AIDS. In this
model, fast disease progression occurs in females only, and is accompanied by an uncontrolled robust mucosal
immune response. All male RMs tested to date exhibit normal (slow/chronic) progression. We hypothesize that
kinetics and magnitude of immune dysregulation that drive viral replication, persistence, and rebound exhibit
sex-based differences and that estrogen may partially contribute to sex difference in immune responses and
viral persistence. We will determine sex-specific immune cellular and molecular determinants relevant to HIV
reservoirs and rebound longitudinally. The contribution of estrogen to sex differences in immune regulation and
viral persistence will also be examined. The proposed work is significant because it promises to provide new
insights into the cross-talk between intestinal immune activation and viral persistence that are differentially
regulated in male and female RMs, which will be critical for developing personalized therapeutic strategies to
reliably halt HIV-associated chronic disease, and to target HIV reservoirs.

Grant Number: 5R01DK130769-05
NIH Institute/Center: NIH
Principal Investigator: Theresa Chang