Project Summary/Abstract
Our overall goal is to determine the long-term consequences of chronic HIV/HCV coinfection as a result of
injection drug use (IDU) and the impact of HCV cure on the relationship of liver fibrosis and immune activation/
dysregulation in reproductively aging HIV-infected women. Liver disease with accelerated liver fibrosis is a major
cause of death in HIV/HCV coinfected adults. Global immune activation may partly explain this accelerated liver
fibrosis. With the advent of interferon-free direct-acting antiviral agents (DAA), a decrease in the burden of liver
disease is expected. It is unknown if, after HCV cure, HIV-associated immune dysfunction impacts liver fibrosis
or if residual liver injury affects immune recovery in reproductively aging HIV/HCV-coinfected women. Estrogen
depletion is associated with increased immune dysfunction and metabolic disruptions, including visceral obesity,
which could impact liver fibrosis. HCV infection has a major impact on immunopathogenesis of HIV and HCV
disease. Our studies show that coinfected women with liver disease as compared to coinfected women without
liver disease, have increased activated CD4+ T cells, and changes in immune regulatory and maturational
pathways critical for immune homeostasis, including regulatory (Treg), senescent, effector memory and effector T
cells. Coinfected women also have higher levels of transforming growth factor-ß (TGF-ß), an immunosuppressive
cytokine critical for Treg differentiation and an important regulator of liver inflammation and fibrosis, as well as IL-
7, which promotes HIV persistence, stimulates HIV replication and HIV reservoirs, and promotes fibrogenesis,
compared to HIV-monoinfected women. Our central hypotheses are that after HCV cure, HIV/HCV-
coinfected women, who are aging, will have impaired liver fibrosis regression, because of HIV-
associated immune dysregulation and increased risk of metabolic perturbations including hepatic
steatosis (or fatty liver). The specific aims are to: (1) Longitudinally examine the short and long-term effects of
HIV and menopause on liver fibrosis after HCV cure in aging HIV/HCV-coinfected women and (2) Determine if
liver fibrosis impacts immune activation and dysregulation after HCV cure in HIV/HCV-coinfected women. HCV-
monoinfected, HIV-monoinfected and uninfected women will serve as controls. We plan to use medication,
menopause, metabolic, and liver fibrosis data, and biorepository samples from the Women's Interagency HIV
Study (WIHS), to accomplish our aims. State- of- the- art clinical and laboratory technologies will evaluate liver
fibrosis and steatosis severity and gene-signature expression to elucidate pathways of immune activation
and dysregulation assessed simultaneously with cellular phenotypic and soluble biomarkers. The WIHS
provides a unique opportunity to tease out the complex contributions of HIV, HCV, liver injury and estrogen
depletion on immunologic markers in women. The proposed studies will help us understand if estrogen
depletion blunts recovery of liver injury after HCV cure and if residual liver injury affects HIV-associated immune
activation/dysregulation. This will help inform strategies for prevention and treatment of liver fibrosis.
