Coinfection with HCV occurs in approximately 30% of HIV-positive persons. It has been well recognized that HIV infection accelerates liver fibrosis progression in the setting of HCV coinfection, although the precise mechanisms underlying this have not been fully elucidated. While great advances have been made in direct acting antiviral (DAA) therapy for HCV, HIV infection alone has increasingly been recognized as a cause of liver fibrosis. Liver disease remains the second most common cause of death in HIV-positive individuals in the active ART era. In addition, progressive hepatic fibrosis is often not recognized until cirrhosis and/or sequelae from its complications have supervened, long after DAAs can reverse the findings. This reality is further compounded by the lack of therapies that halt fibrosis progression. Uncovering the mechanisms underlying fibrosis progression and identifying new targets in HIV infected persons are therefore a high priority. YAP/TAZ are critical intermediates in the Hippo signaling pathway that regulate cell proliferation. In the Hippo ?on? state, YAP/TAZ are phosphorylated in the cytoplasm, leading to inactivation of YAP/TAZ and cell senescence or apoptosis. In the Hippo ?off? state, YAP/TAZ translocates to the nucleus and regulates cell proliferation and fibrogenesis. In addition, YAP/TAZ also respond to extracellular matrix (ECM) cues by sensing the density of the ECM to further augment fibrogenesis. Thus, YAP/TAZ nuclear localization has been induced by stiffer ECM, leading to hepatic stellate cell (HSC) activation and fibrogenesis, further aggravating fibrosis. In earlier work, we demonstrated that HIV accentuates an HCV-driven profibrogenic program, mediated through reactive oxygen species, NF-?B and TGF?1, in both hepatocytes and HSCs. The YAP/TAZ pathway also converges with the TGF?1 pathway, as YAP/TAZ can also act as mechanoreceptors that regulate TGF?1 signaling via direct binding of YAP/TAZ to SMAD proteins, as a function of the stiffness of the ECM in human embryonic stem cells. The importance of the TGF?1 pathway in fibrosis progression in HIV/HCV coinfection suggests that YAP/TAZ plays a critical role in mediating liver disease progression in HIV. To this end, we have demonstrated that HIV can induce YAP/TAZ-regulated profibrogenic gene expression in HSCs, and HCV can do the same in hepatocytes. In addition, several targets upstream of YAP/TAZ are known to bind to HIV and its proteins, further implicating YAP/TAZ in liver disease pathogenesis in HIV. However, detailed studies regarding these associations are lacking. Given the overlap of YAP/TAZ with TGF?1, the mechanoregulatory function of YAP/TAZ, the importance of TGF?1 in HIV-related liver fibrosis, and the known upstream targets of YAP/TAZ that interact with HIV, we hypothesize that YAP/TAZ is pivotal to the pathogenesis of HIV-related liver fibrosis. We will address these relationships through the following Specific Aims: (1) define the contribution of YAP/TAZ pathway activation to hepatic fibrogenesis in the context of HCV and other liver diseases; (2) determine the mechanism(s) by which HIV induces YAP/TAZ activation with/without HCV; and (3) define the contribution of the extracellular matrix to HIV-mediated YAP/TAZ activation. By clarifying the relationship between HIV, HCV, YAP/TAZ, and TGF?, the studies in this proposal are likely to uncover new targets for antifibrotic agents.

Public Health Relevance

HIV infection contributes to an environment that promotes scarring of the liver, in conjunction with hepatitis C and other forms of liver injury. The studies in this proposal will identify key processes that drive liver disease in HIV coinfection. In so doing, they will contribute to identification of new therapeutic strategies for liver diseases associated with HIV that now cause early mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136715-02
Application #
9593497
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lambros, Chris
Project Start
2017-11-03
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114