Fusion-Defective Gibbon Ape Leukemia Virus Vectors Can Be Rescued by Homologous but Not Heterologous Soluble Envelope Proteins

Abstract

Murine leukemia virus (MLV)-derived envelope proteins containing alterations in or adjacent to the highly conserved PHQ motif present at the N terminus of the envelope surface subunit (SU) are incorporated into vector particles but are not infectious due to a postbinding block to viral entry. These mutants can be rendered infectious by the addition of soluble receptor-binding domain (RBD) proteins in the culture medium. The RBD proteins that rescue the infectivity of these defective MLV vectors can be derived from the same MLV or from other MLVs that use distinct receptors to mediate entry. We have now constructed functional immunologically reactive gibbon ape leukemia virus (GALV) envelope proteins, tagged with a feline leukemia virus (FeLV)-derived epitope tag, which are efficiently incorporated into infectious particles. Tagged GALV envelope proteins bind specifically to cells expressing the phosphate transporter protein Pit1, demonstrating for the first time that Pit1 is the binding receptor for GALV and not a coreceptor or another type of GALV entry factor. We have also determined that GALV particles bearing SU proteins with an insertion C-terminal to the PHQ motif (GALV I Virus receptors are the components of cell membranes that allow viral attachment, the first step in infection. It has traditionally been thought that viruses infect and replicate in some cell types, but not others, because of the distribution of specific virus receptors on different cells. Now it is well known that although the presence of specific receptors is critical for viral entry, coreceptors and postentry factors are also important in defining the virus's host range. Some cells express the appropriate receptors but are nevertheless resistant to infection by a specific virus. In many cases, discrepancies between virus receptor distribution and virus host range can be accounted for by cell-specific expression of coreceptors or other ancillary factors required for membrane fusion and internalization of a virus after its initial attachment to its primary receptor. For example, the human CD4 molecule acts as a primary receptor for human immunodeficiency virus type 1 (HIV-1) infection when expressed in human cells but not when expressed in murine cells. When human CD4 is expressed in murine cells, it supports HIV-1 binding but not infection; infection can proceed if such cells express the appropriate coreceptor (reviewed in reference 34). Similarly, Pit1 acts as a primary receptor for feline leukemia virus type T (FeLV-T); however, infection by FeLV-T requires the presence of the FeLIX cofactor (1).In addition to FeLV-T, the phosphate transporter Pit1 has been proposed to serve as the receptor for gibbon ape leukemia virus (GALV) (31), feline leukemia virus subgroup B (FeLV-B) (40), and murine leukemia virus (MLV) 10A1 (30, 43). GALV infects a wide variety of cell types (21) derived from diverse species (20). Because of its broad host range, GALV-based retroviral vectors have been developed for use in both in vivo and ex vivo gene trans...

Identification of receptors for pig endogenous retrovirus

“…2C). Taken together, these results indicate that HuPAR-2 plays a role in binding PERV-A that is analogous to the known multitransmembrane receptors for other gammaretroviruses (15)(16)(17).…”

Genetic and Biochemical Analyses of Receptor and Cofactor Determinants for T-Cell-Tropic Feline Leukemia Virus Infection

“…Indeed, FeLV-B SUs can functionally substitute for FeLIX and mediate FeLV-T infection of cells expressing Pit1 (3). In our studies to date, we have found that only those cofactors with RBDs derived from enFeLV can facilitate infection by FeLV-T. Soluble SUs from amphotropic MLV (A-MLV), GALV, and FeLV-A are not able to facilitate infection in the same way, despite the fact that A-MLV can bind Pit2 and GALV can bind Pit1 (20,29). Unlike FeLV-B, which can utilize both Pit1 and Pit2, FeLV-T is specific in its requirement for Pit1 even when the dual-tropic FeLV-B SUs are supplied as cofactors (29).…”

A soluble envelope protein of endogenous retrovirus (FeLIX) present in serum of domestic cats mediates infection of a pathogenic variant of feline leukemia virus

“…Many studies have revealed that the infectivity abolished by a DH mutation can be restored by the addition of a homologous or heterologous soluble SU or receptor-binding domain (RBD) that contains a complete PHQ motif in trans. This transactivation generally occurs more efficiently via a homologous RBD than a heterologous RBD, with the exception that porcine endogenous retroviruses were much more efficiently transactivated by a heterologous RBD derived from Gibbon ape leukemia virus (Lavillette & Kabat, 2004;Lavillette et al, 2000;Farrell et al, 2002;Lavillette et al, 2002).…”