Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: Implications for the pathogenesis of HIV/hepatitis C virus–induced liver fibrosis†

Over 40 million people are infected with human immunodeficiency virus (HIV) worldwide. Because of their shared routes of transmission, infection with hepatitis C virus (HCV) is common among patients with HIV infection, and approximately 30% of HIV-infected persons in the United States are also infected with HCV.1 The introduction of highly active antiretroviral therapy (HAART) in 1996 changed the natural history of HIV infection and resulted in a dramatic decline in most opportunistic infections. Given their increased survival, HCV-related liver disease has emerged as a major cause of morbidity and mortality among patients infected with HIV. Although the effects of HCV on HIV disease progression are less clear, several studies have demonstrated that HIV infection adversely impacts every stage in the natural history of HCV infection. Infection with HIV enhances HCV transmission, decreases the rates of spontaneous HCV clearance leading to higher rates of chronic hepatitis C infection,2 and is associated with higher HCV RNA loads.3 Once chronic infection is established, HIV/HCV-coinfected patients have higher necro-inflammatory activity on liver biopsies, faster rates of fibrosis progression, and earlier development of end-stage liver disease.4,5 Despite the significant adverse clinical consequences of HIV/HCV coinfection, the underlying molecular mechanisms by which HIV infection impacts HCV disease progression have not been clearly defined. While the host T cell responses appear to be crucial in promoting HCV clearance in acute infection and controlling viral replication and recurrence,6 ultimately these responses fail and the majority of patients become chronically infected. Epidemiological studies support a correlation between lower CD4 cell counts, HCV persistence, and progression of liver disease,4 suggesting that the immunosuppression associated with HIV infection partially contributes to the pathogenesis of chronic liver disease. Whereas higher HCV RNA loads in coinfected patients do not correlate with progression of liver disease, HIV RNA levels correlate with fibrosis progression rates in a dose-dependent fashion.7 Moreover, effective suppression of HIV replication by HAART has been associated with better outcomes.7 Taken together, these findings suggest a direct role for HIV on liver disease progression in coinfected patients. The hepatic stellate cell (HSC) is a central mediator in liver fibrosis. In its quiescent state, it is a vitamin A–rich cell that produces type IV collagen, the collagen characteristic of a normal basement membrane. With injury, such as in chronic hepatitis C, HSCs undergo a process of activation, rendering them susceptible to a variety of stimuli that yield a highly proliferative, contractile, and fibrogenic cell producing predominantly type I collagen, the collagen characteristic of the cirrhotic liver. Activated HSCs express both HIV chemokine coreceptors, chemokine (C-C motif) receptor 5 (CCR5)8 and cysteine-X-cysteine receptor 4 (CXCR4),9 and recent studies suggest effects of HIV envelope protein on HSC responses.10,11 To date there has been no evidence that activated HSCs are a cellular target for HIV infection to account for the accelerated fibrosis observed in coinfected patients. We report that activated HSCs are infectable by HIV, support viral gene expression, and are capable of transmitting infectious virus to susceptible lymphocytes through cell–cell contact. Furthermore, HIV infection of HSCs induces collagen I expression and secretion of the proinflammatory cytokine, monocyte chemoattractant protein 1 (MCP-1). These findings support direct profibrogenic and proinflammatory effects of HIV on stellate cells.