GBV-C and HIV Coinfection May Prove to Expand Our Treatment Options
by Chael Needle

LifeGuide [Treatment Horizons]

Dr. Jack Stapleton, a professor of internal medicine at the University of Iowa Roy J. and Lucille A. Carver College of Medicine and director of the UI AIDS Clinic, recently published findings that built on his research team’s earlier study that suggested GBV-C infection was associated with long-term survival with HIV. GBV-C is a harmless virus in humans, and a commonplace infection. It’s a virus that is usually cleared easily in those who have healthy immune responses, including HIVers within the first six months of infection—a time when the immune system is typically still functioning properly. Once thought to be associated with hepatitis viruses, research interest in GBV-C waned until studies began to accumulate that showed a possible connection to HIV suppression. Earlier research at UI, for example, showed that GBV-C inhibits in vitro HIV from growing in CD4 cells, the same cells where GBV-C grows.

A sticking-point of Dr. Stapleton’s earlier study was that the sample obtained from the UI clinic was rather isolated and the lengths of HIV and GBV-C infection time were unclear—a measure that was needed to make a more informed assessment about long-term coinfection and survival. The NIH facilitated, and eventually funded, the research team’s interaction with the Multicenter AIDS Cohort Study so that they could study GBV-C infection in a wide range of stored samples obtained from HIV seroconverters, thus providing a known time of duration of HIV infection. The study sample, all male, was culled from a group of participants who enrolled between 1984 and 1990 in the cohort study. All had been negative upon enrollment and became HIV-positive during follow-up testing, placing HIV seroconversion within a six- to twelve-month window.

Stapleton et al. found that men persistently coinfected over the long-term with HIV and GBV-C lived longer than men infected only with HIV. Men who were GBV-C-positive five to six years after seroconversion were found to be nearly three times more likely to be alive in subsequent follow-up. Thus, measurement of GBV-C at the later time point was found to be much more predictive of survival than at the eighteen-month time point.

“One thing we don’t know is how many of the people who were GBV-C-positive in that early time point might have acquired GBV-C at the same time that they acquired HIV, and that these men were destined to clear GBV-C early on like most people exposed to the GB virus. Thus, these individuals may not have had the benefit of GBV-C. We’re starting to address those questions by studying samples from more time points on these patients,” says Dr. Stapleton. “We’re especially interested in looking at the people who didn’t make it to the five-year point in the MACS study to see if they cleared GBV-C early on in their HIV infection. [If the virus was cleared] does that explain why there wasn’t a difference [in GBV-C’s inhibitory effects] early on? The current understanding is that you need to carry this virus in order to continue its benefit. These epidemiological studies don’t really show cause and effect, though, but rather show that GBV-C is associated with prolonged survival.”

As Dr. Stapleton outlined, he and others have many possible research directions to follow: Is GBV-C’s efficacy dependent on the mode of HIV transmission? Would sexual, parenteral, or perinatal transmission make a difference, for example? How does GBV-C work on the cellular level? What are the steps of GBV-C replication or what proteins are needed to induce these effects? Does GBV-C alter cytokines in such a way as to change the immune response for the better?

Understanding the mechanism of how GBV-C can influence HIV is key, he says, and this needs to be understood before any talk of how this virus might figure into the design of a new drug or treatment strategy. “Clearly, HAART is far more potent in its effect on HIV than GBV-C. I would never say that GBV-C would be at the same level of inhibition [capability] as HAART,” he says. “On the other hand, if GBV-C can lead to delays in the need for HAART, or potentially alter strategies for using HAART so that you have fewer toxicities from the medication, then that would be a good thing.”

It is also likely that the effect of GBV-C may not lead to rapid development of resistance mutations, a process that often makes treating the disease more challenging. Says Dr. Stapleton: “We think the virus primarily works by altering the cell, not by directly attacking the virus. In that regard, it’s harder for a virus to mutate if there are changes in cellular functions that are inhibitory for HIV. This effect will probably make it harder for the virus to develop resistance.”

Chael Needle wrote about HAART’s effect on viral reservoirs in the April issue.

May 2004