SUMMARY: Individuals coinfected with HIV and hepatitis C virus (HCV) have higher levels of immune activation, and therefore may be at greater risk for disease progression than those with HIV alone who are taking suppressive antiretroviral therapy (ART), according to results from a U.S. veterans study presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco.

By Liz Highleyman

A growing body of evidence links excessive immune activation and inflammation to AIDS-related and non-AIDS disease progression in people with HIV. Since HIV and HCV both trigger immune activation, HIV/HCV coinfected individuals may face an additive risk.

Hans Rempel from the San Francisco Veterans Affairs Medical Center (VAMC) and colleagues hypothesize that having HCV would increase immune activation above that due to HIV alone. They further noted that suppression of HIV viral load with ART slows disease progression in both HIV monoinfected and HIV/HCV coinfected patients.

The investigators devised a chronic immune activation (CIA) index to indicate the level of immune activation by examining unique gene expression profiles of CD14+ monocytes from 44 HIV positive participants (14 with undetectable and 30 with detectable HIV viral load) and 12 HIV negative control subjects. This allowed them to identify 148 genes that were significantly (> 2-fold) up-regulated or down-regulated. Of these 148 genes,19 with > 3-fold up-regulation were included in the CIA index.

Next, they used this index to evaluate expression of these 19 genes in CD14+ monocytes from 12 HIV/HCV coinfected participants on ART with undetectable HIV viral load (< 50 copies/mL) and 14 HCV monoinfected individual. All participants had detectable HCV viral load and none were receiving hepatitis C treatment.

Results

	Higher HIV viral load was associated with increased monocyte activation.
	HIV monoinfected people on ART with suppressed viral load (< 50 HIV RNA copies/ml) had an insignificant increase in monocyte activation compared with control subjects with neither HIV nor HCV.
	HCV monoinfected people had an average immune activation level higher than that of either HIV monoinfected people or uninfected control subjects, though individual levels were variable.
	HIV/HCV coinfected participants with undetectable HIV RNA had greater monocyte activation than people with HIV or HCV monoinfection, again showing individual variability.
	All HIV/HCV coinfected participants with suppressed HIV RNA had monocyte activation profiles indicating greater activation than expected based on their HIV viral load alone.
	2 of these coinfected participants had highly activated monocytes, equivalent to the level expected in a person with a viral load approaching 20,000 copies/mL.
	HIV monoinfected people with high viral load (> 100,000 copies/mL) had the greatest average immune activation of any group, though again there was wide individual variation (there were no coinfected people with high HIV viral load in the study).

These results, the investigators said, "suggest that HCV is amplifying the HIV effect on the immune system."

"Based on immune activation as represented in the CIA index, individuals coinfected with HIV/HCV are at greater risk for disease progression compared to HIV monoinfected individuals despite undetectable HIV viral loads," they concluded. "This elevated immune activation may place these individuals at increased risk for HIV and HCV disease complications."

"Monocyte activation may prove to be a useful metric in determining who is at greatest risk for disease progression," they suggested.

Returning the immune system to normal homeostasis would likely benefit patients with HIV, HCV, or both viruses, they elaborated. " Risk of disease progression is presently measured principally by HIV viral load alone but surprisingly we find that immune activation is a more accurate predictor of HIV disease progression and risk for cognitive impairment than is HIV viral load."

San Francisco VAMC, San Francisco, CA; University of California, San Francisco, CA.

3/12/10

References
H Rempel, B Sun, A Monto, and others. HCV Stimulates HIV Immune Activation in HIV/HCV Co-infected Subjects on HAART. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 672).