Editorial Commentary: Advocating the Concept of GB Virus C Biotherapy Against AIDS

In medical research of epidemiological importance, controversies come and go, but the GB virus (GBV)/human immunodeficiency virus (HIV) confusion is persisting longer than what is reasonable. Taking sides becomes important whenever saving lives is of concern. This is one reason for continued research on the nonpathogenic, “normal flora virus” initially tagged by the misnomer of hepatitis G virus (HGV), but now commonly known as GBV-C. GBV-C infects 1%–5% of the general population in developed nations, and up to 20% of persons in developing countries; it is transmitted via parenteral, vertical, and sexual routes. In the United States alone, 750–1000 individuals are exposed daily to GBV-C through blood transfusion. Based on extensive clinical data, the virus is so common, yet so innocuous, that the Food and Drug Administration has not required blood product screening. This is the only agent knowingly transmitted through iatrogenic interventions in humans, and that fact alone is quite interesting. The interest was amplified in 2001, when 2 independent reports in the New England Journal of Medicine documented positive and dramatic impact of GBV-C coinfection on death rates in AIDS patients. However, some investigators concluded that the GBV-C effect on AIDS progression might be an artifact, resulting from loss of viremia and/or anti–GBV-C antibodies in the late stages of immune suppression. A full-blown controversy arose, which persists today despite results of a 1294-subject meta-analysis, which found highly significant protective effects of persistent GBV-C coinfection among HIV-infected persons. Many investigators remain skeptical concerning the possibility that GBV-C coinfection might be lifesaving in persons with AIDS. Furthermore, the introduction and tremendous success of highly active antiretroviral therapy (HAART) has made the sticky issue of lower priority to researchers because control of AIDS mortality has drastically improved, at least in developed nations. Nonetheless, understanding mechanisms behind this phenomenon of viral interference has tremendous implications for antiviral and vaccine strategic development; therefore, resolving the controversy regarding GBV-C and HIV disease association remains highly important. Pursuit of in vitro models of GBV/ HIV interaction has been highly fertile. GBV-C is lymphotropic, infecting both CD4 and CD8 T cells. Although inefficient, peripheral blood mononuclear cell cultures are infected by GBV-C in vitro. CD4 T-cell infection by GBV-C in vitro represses interleukin 2 (IL-2) responsiveness, as well as the ability of HIV to cause infection and cell death. This phenomenon is referred to as viral interference and is not uncommon. At least 2 GBV-C gene products can independently alter CD4 T cells to make them less permissive for HIV. The envelope gene E2 encodes a product that interferes with HIV entry and fusion, potentially via interaction with HIV gp41 and an unidentified host membrane component. The E2 protein also blocks the proliferative effect of IL-2 on CD4 T cells, which is detrimental to HIV because the latter virus replicates optimally in activated cells. The GBV-C NS5A gene product downregulates the HIV coreceptor CXCR4, and GBV-C is also a potent inducer of at least 3 hostcell molecules that are inhibitory to HIV via coreceptor ligand interactions. Thus, molecular evidence for a strong, negative effect of GBV-C on HIV success is readily evident from in vitro models. It is therefore not surprising that an inverse relationship between GBV-C and HIV load has been observed in several studies. Received 11 June 2012; accepted 13 June 2012; electronically published 2 July 2012. Correspondence: David Gretch, MD, PhD, Harborview Medical Center NJB-345, Box 359743, 325 Ninth Ave, Seattle, WA 98104 ([email protected]). Clinical Infectious Diseases 2012;55(7):1020–1 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please email: journals.permissions@ oup.com. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/cis591