GB virus C (GBV-C) is a nonpathogenic lymphotropic virus that replicates in B and T lymphocytes. Infection with GBV-C is documented worldwide and is common: between 1% and 5% of healthy blood donors are viremic at the time of donation. Antibodies to GBV-C proteins are not usually detected during viremia, and antibodies to the GBV-C envelope glycoprotein E2 develop following the clearance of viremia. Although GBV-C viremia may persist for decades, viremia usually clears within 2 years following infection in the majority of individuals infected by blood transfusion. A chimpanzee variant of GBV-C, designated GBV-Ccpz, is found in captive and noncaptive chimpanzees and its prevalence and natural history are uncharacterized. GBV-C research was initially performed by viral hepatitis research groups because it was predicted to cause hepatitis. The realization that GBV-C did not cause hepatitis resulted in a marked reduction in research activity. Because Hepatitis C virus co-infection worsens the clinical course of HIV-infected patients, researchers hypothesized that the related virus, GBV-C, may impact HIV disease. In 1998, researchers found that HIV-infected individuals who were co-infected with GBV-C survived longer than those without GBV-C. These findings provide the rationale for examining the relationship of GBV-C and HIV and the development of GBV-C as a novel therapeutic for HIV. GBV-C infection of PBMCs inhibits the replication of HIV isolates and one of the mechanisms for this is the induction of the release of soluble ligands for HIV entry receptors (RANTES, macrophage inflammatory proteins (MIP)-1α and MIP-1β and SDF-1) by GBV-C. The GBV-C envelope glycoprotein E2 contributes directly to the inhibition of HIV infection. Incubation of recombinant E2 with PBMCs at 4°C prior to HIV infection results in a decrease in HIV replication, and only HIV gp160 enveloped pseudoparticle transduction, not VSV-G enveloped pseudoparticle transduction, is inhibited by GBV-C E2. This suggests that GBV-C E2 inhibits HIV infection at an entry step when the HIV gp160 envelope protein interacts with cellular receptors and membranes. How GBV-C E2 interacts with cellular surfaces and which cellular proteins are utilized for GBV-C binding and entry are unknown. Here, we characterize GBV-C E2 binding to human PBMCs, murine cells, and multiple transformed cell lines to identify the PBMC subset which E2 binds and to identify candidate cellular receptors involved in GBV-C binding and entry. Understanding how GBV-C E2 interacts with cellular surfaces is critical to determining how it inhibits HIV entry. Anti-GBV-C E2 antibodies are also associated with improved survival in HIV-infected individuals. Recent studies demonstrated that anti-E2 antibodies neutralize HIV infection in vitro and immunoprecipitate HIV virions. In these studies, we describe how anti-E2 antibodies immunoprecipitate retroviral particles regardless of the specific viral envelope protein on the surface, but only neutralize particles bearing the HIV gp160 envelope protein. We also found that the cellular antigen recognized by anti-E2 antibodies is accessible only in permeabilized cells and not on the cell surface. These studies provide insight into the HIV-inhibitory mechanisms of anti-E2 antibodies, which should aid in the development of GBV-C E2 as an immunogen in an HIV vaccine. Finally, no animal models exist for studying GBV-C infection or GBV-C vaccines as HIV therapeutics in vivo. We examined the natural history GBV-Ccpz in a captive chimpanzee population, and found that the prevalence of GBV-Ccpz viremia and anti-E2 antibodies, as well as the length of persistent infection, were similar to those found in healthy human blood donors. The GBV-Ccpz 5#8217;ntr and RdRp sequences from chimpanzee subspecies troglodytes and verus shared a high level of sequence identity and indicate that the chimpanzee variant should be designated GBV-Ccpz rather than the currently used GBV-Ctrog. These findings demonstrate that GBV-Ccpz viremia and E2 antibody status should be tested in animals involved in clinical research trials because affected animals may have altered responses to GBV-C infection or HIV vaccines, and that the chimpanzee would be a good animal model in which to study GBV-C infection.