HIV and Hepatitis C Virus Coinfection May Increase Death of CD4 T-cells

		SUMMARY: Dual infection with HIV and hepatitis C virus (HCV) may promote heightened apoptosis, or programmed death, of CD4 T-cells, according to a poster presented last month at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) in Vienna. This may help explain the finding in some studies that HIV/HCV coinfected people tend to experience more rapid HIV disease progression and have smaller CD4 cell gains on antiretroviral therapy (ART) than those with HIV alone.

By Liz Highleyman

C. Körner and colleagues from the University of Bonn in Germany conducted a laboratory study to shed further light on their previous finding that HIV/HCV coinfected individuals have greater CD4 cell apoptosis -- a type of "cell suicide" -- than HIV monoinfected individuals.

The researchers suggested that this might be a potential mechanism contributing to accelerated progression to AIDS and increased mortality in patients with HIV/HCV coinfection. Some studies have shown that coinfected individuals experience faster HIV disease progression, but others have not observed this correlation. Similarly, some studies have shown that coinfected people gain fewer CD4 cells that HIV monoinfected people after starting ART, but others have seen no difference.

In this analysis, the researchers hypothesized that receptor-induced apoptosis might be a potential cause of this effect, leading them to look at expression and function of Fas ligand, a transmembrane protein that causes apoptosis when it binds with its corresponding Fas "death receptor."

The investigators analyzed blood samples from 130 participants, including 15 with HCV only, 54 with HIV only, 61 with HIV/HCV coinfection, and 15 healthy control subjects with neither virus.

Serum levels of soluble Fas ligand were detected using an ELISA assay. Surface expression of Fas ligand and Fas receptors on CD4 T-cells was determined using flow cytometry. Fas ligand-induced apoptosis was analyzed by incubating isolated peripheral white blood cells with recombinant human Fas ligand and measuring subsequent CD4 cell death.

Results

	HIV and HCV monoinfection were both associated with significantly greater Fas receptor expression on CD4 cells relative to people with neither virus (60, 63, and 38, respectively).
	The highest Fas receptor expression, however, was seen in HIV/HCV coinfected patients (88).
	Fas receptor expression was strongly correlated with low CD4 cell counts in HIV positive patients.
	In contrast, elevated levels of soluble and cellular Fas ligand were seen only in HIV positive people (with or without HCV), not in those with HCV monoinfection.
	Enhanced Fas receptor expression in HIV/HCV coinfected patients rendered CD4 cells significantly more susceptible to Fas ligand-induced apoptosis.
	Effective ART normalized serum levels of soluble Fas ligand and expression of cellular Fas ligand in HIV monoinfected and HIV/HCV coinfected patients.
	Fas receptor expression, however, decreased only slightly with ART, and remained significantly elevated relative to healthy control subjects.

"Our findings suggest a synergistic mechanism in HIV/HCV coinfection between upregulation of Fas [receptor] expression on CD4+ T-cells and HIV-induced elevated levels of cellular and soluble Fas ligand," the investigators concluded. "Together, both effects contribute to enhanced apoptosis of CD4+ T-cells, which has been observed in HIV/HCV coinfection."

Internal Medicine I, University of Bonn, Bonn, Germany.

5/4/10

Reference
C Körner, F Tolksdorf, D Schulte, and others. Hepatitis c co-infection sensitizes CD4+ T cells towards Fas-induced apoptosis in HIV-positive patients. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).