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

Abstract

Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) develop more rapid fibrosis than those infected with HCV only. In HIV/HCV‐coinfected patients, fibrosis progression correlates with HIV RNA levels, suggesting a direct role of HIV in liver fibrogenesis. Chemokine (C‐C motif) receptor 5 (CCR5) and cysteine‐X‐cysteine receptor 4 (CXCR4), the two major coreceptors required for HIV entry into cells, are expressed on activated hepatic stellate cells (HSCs), the principle fibrogenic cell type in the liver. We therefore examined whether HIV can infect HSCs, explored the potential mechanisms of viral entry, and assessed the impact of infection as reflected by the ability of HSCs to transfer virus to T lymphocytes and elicit a proinflammatory and profibrogenic response. We report that the laboratory‐adapted viruses HIV‐IIIB (CXCR4‐tropic or X4) and HIV‐BaL (CCR5‐tropic or R5) and primary HIV isolates can infect both a human stellate cell line, LX‐2, and primary human HSCs. HIV entry and gene expression in HSCs was confirmed using HIV–green fluorescent protein (GFP) expression viral constructs in the presence or absence of the reverse‐transcriptase inhibitor azidothymidine. CD4 expression on a subset of primary HSCs was demonstrated using fluorescence‐activated cell sorting and immunofluorescence staining. Blocking experiments in the presence of anti‐CD4, anti‐CXCR4, and anti‐CCR5 revealed that HIV entry into HSCs is predominantly CD4/chemokine coreceptor–independent. HIV infection promoted HSC collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein‐1. Furthermore, infected LX‐2 cells were capable of transferring GFP‐expressing virus to T lymphocytes in a coculture system. Conclusion: Taken together, our results suggest a potential role of HIV in liver fibrosis/inflammation mediated through effects on HSCs. The role of early highly active antiretroviral therapy initiation in patients with HIV/HCV coinfection warrants further investigation. (HEPATOLOGY 2010)

Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)—Newer Insights into Pathogenesis and Emerging Newer Treatment Options

“…[40][41][42][43][44][45] Enteropathy is a well established feature of HIV infection. Infection of hepatic stellate cells by HIV may contribute to the pathogenesis of portal venous and sinusoidal endothelial injury via stimulation of prothrombotic cytokines such as endothelin-l, inerleukins-l and 6 and platelet derived growth factor 46 and protein S deficiency. 47 Although untested it may also be that stellate cell infection by HIV may contribute by diminishing production of ADAMTS 13 (see later).…”

The absence of the human platelet antigen polymorphism effect on fibrosis progression in human immunodeficiency virus-1/hepatitis C virus coinfected patients

“…However, the chemokine coreceptors CCR5 and CXCR4, which allow the HIV to enter its target cells, are expressed on hepatocytes and stellate cells. The interactions between the HIV and these cells via CCR5 and CXCR4 induce cell signaling (25) (26) (27) , which subsequently leads to the greater expression of pro-fi brogenic factors, such as TGF-β1, which Demographic characteristics of the human immunodefi ciency virus-1/hepatitis C virus-coinfected patients (n = 36) are involved in the activation of the stellate cells. Thus, the presence of HIV-1 and the activation of signaling pathways via non-integrin receptors may lead to the greater stimulation of the stellate cells as a consequence of the increased expression of TGF-β, which would offset the effect of the HPA polymorphism on the progression of hepatic fi brosis.…”

HIV-1 Pathogenesis: The Virus

“…Viral DNA, RNA, and protein have been detected in liver samples from HIV-1-infected subjects (Housset et al 1990;Cao et al 1992;van't Wout et al 1998). In cell culture systems, HIV-1 has been reported to infect Kupffer cells (Schmitt et al 1990) and stellate cells (Tuyama et al 2010). HIV-1 infection of stellate cells may contribute to liver fibrosis by promoting collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1 (Tuyama et al 2010).…”

“…In cell culture systems, HIV-1 has been reported to infect Kupffer cells (Schmitt et al 1990) and stellate cells (Tuyama et al 2010). HIV-1 infection of stellate cells may contribute to liver fibrosis by promoting collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1 (Tuyama et al 2010). Another proposed pathogenic mechanism is induction of apoptosis in hepatocytes after exposure to HCV E2 and HIV gp120 (Munshi et al 2003;Vlahakis et al 2003).…”