# HIV, HCV, Hippo, and Liver Disease Progression

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $642,162

## Abstract

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-κB and TGFβ1, in both hepatocytes and HSCs. The YAP/TAZ pathway also converges with the
TGFβ1 pathway, as YAP/TAZ can also act as mechanoreceptors that regulate TGFβ1 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 TGFβ1 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 TGFβ1, the
mechanoregulatory function of YAP/TAZ, the importance of TGFβ1 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 contribut...

## Key facts

- **NIH application ID:** 9814095
- **Project number:** 5R01AI136715-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** RAYMOND T CHUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $642,162
- **Award type:** 5
- **Project period:** 2017-11-03 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814095

## Citation

> US National Institutes of Health, RePORTER application 9814095, HIV, HCV, Hippo, and Liver Disease Progression (5R01AI136715-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9814095. Licensed CC0.

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