Specificity in receptor usage by T-cell-tropic feline leukemia viruses: Implications for the in vivo tropism of immunodeficiency-inducing variants

Cytopathic, T-cell-tropic feline leukemia viruses (FeLV-T) evolve from FeLV -A in infected animals and demonstrate host cell specificities that are dis tinct from those of their parent viruses. We recently identified two cellul ar proteins, FeLIX and Pit1, required for productive infection by these imm unodeficiency-inducing FeLV-T variants (M.M. Anderson, A.S. Lauring, C.C. B urns, and J. Overbaugh, Science 287:1828-1830, 2000). FeLV-T is the first e xample of a naturally occurring type C retrovirus that requires two protein s to gain entry into target cells. FeLIX is an endogenous protein that is h ighly related to the N-terminal portion of the FeLV envelope protein, which includes the receptor-binding domain. Pit1 is a multiple-transmembrane pho sphate transport protein that also functions as a receptor for FeLV-B. The FeLV-B envelope gene is derived by recombination with endogenous FeLV-like sequences, and its product can functionally substitute for FeLIX in facilit ating entry through the Pit1 receptor. In the present study, we tested othe r retrovirus envelope surface units (SUs) with their cognate receptors to d etermine whether they also could mediate infection by FeLV-T. Cells were en gineered to coexpress the transmembrane form of the envelope proteins and t heir cognate receptors; or SU protein was added as a soluble protein to cel ls expressing the receptor. Of the FeLV, murine leukemia virus, and gibbon ape leukemia virus envelopes tested, we found that only those with receptor -binding domains derived from endogenous FeLV could render cells permissive for FeLV-T. We also found that there is a strong preference for Pit1 as th e transmembrane receptor. Specifically, FeLV-B SUs could efficiently mediat e infection of cells expressing the Pit1 receptor but could only inefficien tly mediate infection of cells expressing the Pitt receptor, even though th ese SUs are able to bind to Pitt. Expression analysis of feline Pit1 and Fe LIX suggests that FeLIX is likely the primary determinant of FeLV-T tropism . These results are discussed in terms of current models for retrovirus ent ry and the interrelationship among FeLV variants that evolve in vivo.