HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV (estimated at 53,600/cases year in 2006) and the longer life expectancy due to effective antiretroviral therapies. As HIV patients continue to live longer in the setting of effective ART, liver disease has become the leading cause of non-AIDS related mortality. Given the shortage of donor organs, the economic burden of transplant, and the aging cohort of HIV+ patients with underlying liver disease, there is an urgent need for the development of anti-fibrotic approaches for this population. This proposal focuses on understanding how HIV interacts with the activated hepatic stellate cell (HSC), which is thought to be a key cell responsible for fibrosis. Our long term goal is to determine how HIV accelerates fibrosis in all forms of liver disease through interactions with activated HSCs.
The specific aims of the proposal are to: 1) Establish the pro-fibrogenic effects of HIV gp120 on HSCs in vitro and in vivo; 2) Determine if HIV promotes TGFβ1 production by Kupffer cells (liver macrophages), which leads to paracrine stimulation of collagen I expression by activated HSCs; 3) Examine if activated HSCs support HIV replication in vivo and/or transfer HIV to primary CD4+ T cells. Understanding how HIV accelerates liver fibrosis will lead to innovative anti-fibrotic approaches for HIV+ patients with underlying chronic liver injury. Reducing this burden of liver disease will substantially improve the health and survival of patients on long-term HAART and findings from this proposal will contribute knowledge important in achieving this goal.
Liver failure due to accelerated fibrogenesis in patients with HCV or HBV-related liver injury is a leading cause of death in HIV-infected individuals in the era of effective antiretroviral therapies. Given the shortage of donor organs, there is an urgent need to develop anti-fibrotic approaches for this population.
