Can two viruses be better than one?

GB virus C (GBV-C) is an RNA virus that is closely related to the hepatitis C virus. Although originally detected in persons with non-A, non-B hepatitis, GBV-C has not been associated with hepatitis or any other disease in humans. Traditional transmission patterns (parenteral, sexual, or vertical) have been demonstrated, and infection is common worldwide. Parenteral transmission dominates with a high seroprevalence among intravenous drug users.

Charles John Palenik, MS, PhD, MBA

GB virus C (GBV-C) is an RNA virus that is closely related to the hepatitis C virus. Although originally detected in persons with non-A, non-B hepatitis, GBV-C has not been associated with hepatitis or any other disease in humans. Traditional transmission patterns (parenteral, sexual, or vertical) have been demonstrated, and infection is common worldwide. Parenteral transmission dominates with a high seroprevalence among intravenous drug users.

GBV-C appears to replicate in peripheral lymphocytes with viremias lasting many years. However, most (60 to 75 percent) immunocompetent persons spontaneously clear themselves of GBV-C. Clearance is usually associated with the appearance of antibodies against a GBV-C envelope glycoprotein, E2.

Over the last few years, the interactions between GBV-C and HIV have been debated. A number of studies indicated a surprising survival benefit among persons who were coinfected vs. those who were infected only with HIV. Other studies did not demonstrate a survival advantage. The most comprehensive study (Williams GF et al., Persistent GB virus C infection and survival in HIV-infected men. N Eng J Med 2004;350:981-990) to date appeared in March 2004. The study thoroughly investigated data from the Multicenter Acquired Immunodeficiency Syndrome Cohort Study, in which 271 participants were HIV positive and had a current or previous GBV-C infection. GBV-C infection was based primarily on the presence of antibodies to E2 or the presence of GBV-C RNA. Men were evaluated twice — 12-18 months after HIV seroconversion (early visit), and then five to six years after the date of seroconversion (late visit).

Significant survival advantage of coinfection could not be noted during the early visit. Nevertheless, men without GBV-C RNA five to six years after HIV seroconversion were 2.78 times as likely to die as men with persistent GBV-C viremias. Loss of GCV-C RNA was a strong predictor of death. Survival rates 10 to 11 years after HIV seroconversion in men who were positive for GBV-C RNA at both 12 to 18 months and five to six years was 75 percent, as compared with 39 percent among those who were persistently negative for GBV-C RNA and 16 percent for those who lost their GBV-C infection sometime during the first five to six years after seroconversion.

The results involved men who acquired HIV through sexual contact before effective antiretroviral therapy became readily available. The effects of coinfection among women, those receiving drug therapy, or people infected parenterally are not known.

The mechanism associated with the protective effect has yet to be determined, but there are a number of possibilities. Research suggests direct viral interference — competition to attach to the same host cells. Another possibility is that HIV replication may be directly reduced by GBV-C. Both GBV-C and HIV infect and replicate in peripheral lymphocytes. GBV-C could then affect various stages of the HIV life cycle. This could involve inhibition of HIV penetration into host cells, competition for internal host enzymes, formation of HIV proviruses, viral transcription and translation, and viral assembly and release.

Persistent coinfection with GBV-C may be a sign of immunologic or some other host characteristic that confers relative resistance to the advancement of HIV disease. A key missing piece is how, if, and when E2 antibodies form, and why some people can clear GBV-C without forming antibodies.

The WHO estimates that 40 million people are living with HIV worldwide. Approximately 2.5 million are children under the age of 15. Globally, an estimated 5 million persons are infected each year, while slightly more than 3 million died of AIDS in 2003. In the developing world, less than 7 percent of people infected with HIV have access to antiretroviral therapy.

In the United States, an estimated 850,000 to 950,000 persons are living with HIV. Approximately one-fourth are unaware of their infection, and thus are not receiving treatment or preventive services.

More could be learned about the progression of HIV by studying the interactions of GBV-C and HIV infections. There is a long history of one virus augmenting the pathogenesis of another virus, including HIV. The opposite outcome, where a person benefits from a dual infection, has never been proven. New approaches including potential GBV-C-related disease-modifying treatments or vaccines offer hope in a world where access to effective drug therapies is a luxury. Further information is available on the OSAP Web site — www.osap.org.

Dr. Charles John Palenik is an assistant director of Infection Control Research and Services at the Indiana University School of Dentistry. He serves on the Executive Board of OSAP, dentistry's resource for infection control and safety.

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