GB virus type C interactions with HIV: the role of envelope glycoproteins

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Abstract
Summary. GB virus C/hepatitis G virus (GBV‐C/HGV) is the most closely related human virus to hepatitis C virus (HCV). GBV‐C is lymphotropic and not associated with any known disease, although it is associated with improved survival in HIV‐infected individuals. In peripheral blood mononuclear cells, GBV‐C induces the release of soluble ligands for HIV entry receptors (RANTES, MIP‐1a, MIP‐1b and SDF‐1), suggesting that GBV‐C may interact with lymphocytes to induce a chemokine and/or cytokine milieu that is inhibitory to HIV infection. Expression of GBV‐C envelope glycoprotein E2 in CD4+ T cells or addition of recombinant E2 to CD4 cells recapitulates the HIV inhibition seen with GBV‐C infection. Like HCV E2, GBV‐C E2 is predicted to be post‐translationally processed in the endoplasmic reticulum and is involved with cell binding. The C‐termini of GBV‐C E1 and E2 proteins contain predicted transmembrane domains sharing features with HCV TM domains. To date, cellular receptor(s) for GBV‐C E2 have not been identified. GBV‐C E2‐mediated HIV inhibition is dose‐dependent and HIV replication is blocked at the binding and/or entry step. In addition, a putative GBV‐C E2 fusion peptide interferes with HIV gp41 peptide oligomerization required for HIV‐1 fusion, further suggesting that GBV‐C E2 may inhibit HIV entry. Additional work is needed to identify the GBV‐C E2 cellular receptor, characterize GBV‐C E2 domains responsible for HIV inhibition, and to examine GBV‐C E2‐mediated fusion in the context of the entire envelope protein or viral‐particles. Understanding the mechanisms of action may identify novel approaches to HIV therapy.