By Liz Highleyman

Numerous studies -- though not all -- indicate that HIV-HCV coinfected patients experience more rapid liver disease progression and do not respond as well to interferon-based therapy for hepatitis C compared to people with HCV alone.

Four studies presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007) provide information about biological mechanisms that may contribute to these differences between coinfected and monoinfected individuals.

HIV in Hepatic Stellate Cells

Some studies have shown that liver fibrosis progression is worse in coinfected patients with higher HIV viral load, suggesting that HIV may play a direct role in fibrogenesis.

In a laboratory study (abstract LB3), researchers examined whether strains of HIV that use 2 different co-receptors to enter host cells (CCR5-tropic HIV-IIIB and CXCR4-tropic HIV-Bal) were able to enter hepatic stellate cells, a type of liver cell that produce the extracellular matrix proteins responsible for fibrosis.

The same team previously reported that hepatic stellate cells express the CCR5 co-receptor, and at AASLD they reported that these cells also express CXCR4 (abstract 1400).

The investigators found that HIV infects, expresses its genes, and replicates within hepatic stellate cells, as demonstrated by significant concentrations of the HIV p24 protein. Although stellate cells also express the CD4 receptor, HIV-IIIB was able to enter these cells independent of CD4.

HIV infection of the stellate cells promoted cell activation and stimulated a 1.6-fold increase in production of collagen and a 1.5-fold increase in production of alpha-SMA, a protein associated with fibrosis. Collagen and alpha-SMA production also increased (by 2.1-fold and 1.4-fold, respectively) when the stellate cells were exposed to the HIV gp120 envelope glycoprotein, even if HIV did not enter the cells.

“HIV enters and actively replicates within hepatic stellate cells independent of CD4,” the researchers concluded. “Both viral entry as well as exposure of cells to viral envelope glycoproteins can promote activation and collagen induction in hepatic stellate cells. These results suggest that direct infection or Env-mediated activation of hepatic stellate cells may contribute to rapid development of fibrosis in patients coinfected with HIV-HCV.”

In a related study (abstract 125), Italian researchers also demonstrated that in vitro exposure of hepatic stellate cells to gp120 from CCR5-tropic HIV strains (CN54 and SF162) at concentrations of 10-1000 ng/mL led to cell activation, increased secretion and gene expression of the pro-inflammatory chemokine MCP-1, and increased production of collagen.

“This study shows that HIV-gp120 modulates different aspects of hepatic stellate cells biology, including stimulation of chemotaxis, and increased expression of collagen and pro-inflammatory chemokines,” the researchers stated. “These results suggest a direct role of HIV proteins in the process of liver fibrogenesis.”

HIV Promotes HCV Replication

HIV also may play a role in stimulating HCV replication, according to another presentation (abstract 469).

Researchers from Harvard University and Massachusetts General Hospital sought to determine whether HIV and its individual proteins increase HCV levels. They incubated inactivated HIV and recombinant HIV proteins (gp120, Gag, Tat, Pol, and Rev) in OR6 genotype 1b HCV replicon cells and infectious HCV JFH1 cells for 48 hours.

They found that HCV replication increased by more than 2-fold from baseline in the presence of gp120. However, there were no changes in HCV RNA or core protein levels in the presence of any of the other HIV proteins. Further, HIV gp120 significantly increased expression of transforming growth factor-beta-1 (TGF-beta-1), a cytokine that promotes cell proliferation.

11/27/07

References

AC Tuyama, F Hong, AD Schecter, and others. HIV entry and replication in stellate cells promotes cellular activation and fibrogenesis: Implications for hepatic fibrosis in HIV/HCV co-infection. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston. November 2-6, 2007. Abstract LB3.