Mechanisms of Accelerated Fibrosis in HIV-HCV and HIV-HBV Coinfected Individuals

By Liz Highleyman

HIV positive people with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection tend to experience more rapid liver disease progression, by the underlying mechanisms are not fully understood.

Two studies looking at the effects of HIV on HBV and HCV were presented last month at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) in Copenhagen.

HIV in HBV Cell Lines

D.M. Iser from the University of Melbourne in Australia and colleagues developed an in vitro model to assess the effects of HIV on HBV replication and hepatic stellate cell function. Stellate cells are support cells in the liver that, when activated during liver injury, produce collagen and other components of scar tissue that over time replace normal liver tissue, resulting in fibrosis and eventually cirrhosis.

In this laboratory study, human hepatic cell lines chronically infected with HBV (Hep3B and AD38 cells) and without HBV (HuH7 and HepG2 cells) were infected with stocks of HIV (NL4-3 and AD8). Cells were also infected with an engineered pseudo-virus containing vesicular stomatitis virus (VSV) envelope protein and HIV, but expressing green fluorescent protein (GFP) in place of the HIV nef protein. In addition, human hepatic stellate cells were alsoinfected with HIV (NL4-3 and NL4-3 containing GFP).

Results

Low-level HIV infection of hepatic cell lines was demonstrated by increasing reverse transcriptase activity in the cell cultures following infection with either NL4-3 or AD8.

HIV infection was also observed in hepatic stellate cells exposed to NL4-3 and AD8.

Infected cells expressing GFP were detected by fluorescent microscopy and flow cytometry.

High level HIV infection in hepatic cell lines was established using the VSV/HIV pseudo-virus.

HBV DNA levels in cell material from AD38 cells infected with the VSV/HIV pseudo-virus were similar to levels in uninfected control cells.

However, hepatitis B surface antigen (HBsAg) levels increased in cell culture material from AD38 cells infected with the VSV/HIV pseudo-virus compared with uninfected control cells.

"HIV infects both hepatic and stellate cell lines," the researchers concluded.

"High-level HIV infection with a pseudotyped virus did not affect levels of HBV DNA from hepatic cells chronically infected with HBV, but altered HBsAg production and release in the supernatant," they continued. "Future work will explore the mechanism of HIV infection of these cells and determine the combined effect of HIV and HBV on markers of hepatic stellate cell activation."

Department of Medicine, University of Melbourne, Melbourne, Australia; St. Vincent's Hospital, Melbourne, Australia; Infectious Diseases Unit, Alfred Hospital, Melbourne, Australia; Department of Medicine, Monash University, Melbourne, Australia; Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia.

HCV in Hepatic Stellate Cells

S. Galastri from the University of Florence and colleagues sought to understand the mechanisms underlying accelerated fibrogenesis (production of fibrous tissue in the liver) in HIV-HCV coinfected individuals. To this end, they assessed the biological effects of the HIV gp120 envelope protein on cultured human hepatic stellate cells.

Stellate cells were isolated from normal human liver tissue and used in their myofibroblast-like phenotype. These cells were exposed to concentrations of HIV gp120 (10-1000 ng/mL) previously shown to influence the biology of different cell types. The researchers assessed hepatic stellate cell migration, expression and secretion of cytokines and type I procollagen, and intracellular signaling pathways.

Results

Transcripts for the chemokine receptors CCR5 and CXCR4, which may bind HIV-gp120, were expressed by human hepatic stellate cells.

When exposed to 2 different types of macrophage-tropic (M-tropic) gp120 (CN54 or SF162), which typically uses the CCR5 coreceptor, a significant increase in hepatic stellate cell chemotaxis (chemically induced migration) was observed.

However, T-tropic HIV gp120, which typically uses the CXCR4 coreceptor, produced more modest effects.

Protein denaturation prevented the effects of gp120 on cell migration, indicating a specific action.

Incubation of hepatic stellate cells with gp120 significantly increased secretion and gene expression of monocyte chemoattractant protein-1 (MCP-1), but only modestly increased secretion of type I procollagen.

The biological effects of gp120 were associated with an increase in phosphorylation of p38MAPK and NF-kappa-B, which promotes pro-inflammatory stimuli in hepatic stellate cells, and with activation of Akt, which is implicated in cell migration.

When hepatic stellate cells were pre-treated with the CCR5 antagonist TAK-779, gp120-inducedc ell migration was marked inhibited.

Migration was also blocked by the PI3K antagonist LY294002.

"This study show that HIV-gp120 exerts multiple effects on human hepatic stellate cells, including stimulation of migration and increased expression of MCP-1 and type I procollagen," the investigators concluded.

"These actions are mediated via activation of the chemokine receptor CCR5," they continued. "These data suggest a direct role of HIV in the process of hepatic fibrogenesis."

University of Florence, Florence, Italy; University of Pavia, Pavia, Italy; Istituto Superiore di Sanità, Roma, Italy.

5/15/09

References

S Galastri, R Bruno, P Sacchi, and others. The Chemokine Receptor CCR5 Mediates the Profibrogenic Actions of the HIV Envelope Protein Gp120 in Human Hepatic Stellate Cells. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

DM Iser, A Solomon, S Saleh, and others. HIV Infection of Chronically Hepatitis B Virus (HBV)-Infected Human Hepatic and Stellate Cell Lines: Implications for Pathogenesis of HIV-HBV Co-Infection. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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Highlights of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2009) - Coverage by HIV and Hepatitis.com, February 8 - 11, 2009, Montreal