Shared usage of the chemokine receptor CXCR4 by the feline and human immunodeficiency viruses

Abstract

Feline immunodeficiency virus (FIV) induces a disease state in the domestic cat that is similar to AIDS in human immunodeficiency virus (HIV)-infected individuals. As with HIV, FIV can be divided into primary and cell culture-adapted isolates. Adaptation of FIV to replicate and form syncytia in the Crandell feline kidney (CrFK) cell line is accompanied by an increase in the net charge of the V3 loop of the envelope glycoprotein, mirroring the changes observed in the V3 loop of HIV gp120 with the switch from a non-syncytium-inducing phenotype to a syncytium-inducing phenotype. These data suggest a common mechanism of infection with FIV and HIV. In this study, we demonstrate that cell culture-adapted strains of FIV are able to use the ␣-chemokine receptor CXCR4 for cell fusion. Following ectopic expression of human CXCR4 on nonpermissive human cells, the cells are able to fuse with FIV-infected feline cells. Moreover, fusion between FIV-infected feline cells and CXCR4-transfected human cells is inhibited by both anti-CXCR4 and anti-FIV antibodies. cDNAs encoding the feline CXCR4 homolog were cloned from both T-lymphoblastoid and kidney cell lines. Feline CXCR4 displayed 94.9% amino acid sequence identity with human CXCR4 and was found to be expressed widely on cell lines susceptible to infection with cell culture-adapted strains FIV. Ectopic expression of feline CXCR4 on human cells rendered the cells susceptible to FIV-dependent fusion. Moreover, feline CXCR4 was found to be as efficient as human CXCR4 in supporting cell fusion between CD4-expressing murine fibroblast cells and either HIV type 1 (HIV-1) or HIV-2 Env-expressing human cells. Previous studies have demonstrated that feline cells expressing human CD4 are not susceptible to infection with HIV-1; therefore, further restrictions to HIV-1 Env-dependent fusion may exist in feline cells. As feline and human CXCR4 support both FIV-and HIVdependent cell fusion, these results suggest a close evolutionary link between FIV and HIV and a common mechanism of infection involving an interaction between the virus and a member of the seven-transmembrane domain chemokine receptor family of molecules.

Palmitoylation of the feline immunodeficiency virus envelope glycoprotein and its effect on fusion activity and envelope incorporation into virions

“…After 48 h of coculture, cells were stained for b-galactosidase activity and scored for syncytia formation. This cellcell fusion assay is based on the facts that the FIV Petaluma isolate is independent of the CD134 primary receptor for cell entry (Shimojima et al, 2004) and that FIV can efficiently use human CXCR4 (Poeschla and Looney, 1998;Willett et al, 1997). Under the experimental conditions described above, 293T cells expressing wild-type Env yielded 763769 blue syncytia per well (average of three independent experiments,7SD).…”

Vaccine-induced enhancement of viral infections

“…vaccination) would provide the virus with an ideal opportunity for its replication [109]. Furthermore, the FIV coreceptor CXCR4 molecule is expressed on activated T-, B-cells and monocytes [110]. It was demonstrated that increased expression of CXCR4 in cell lines resulted in enhanced FIV replication in vitro [111].…”

Peptides derived from HIV-1, HIV-2, Ebola virus, SARS coronavirus and coronavirus 229E exhibit high affinity binding to the formyl peptide receptor

“…One possible reason for the existence of polymorphisms is that polymorphisms might prevent pathogens from binding to receptors and using them as an entry point into cells. Several G protein-coupled receptors have been used by pathogens as a point of entry into cells and the use of CCR5 and CXCR4 as co-receptors for HIV-1 and CXCR4 as a co-receptor for FIV are notable examples [14][15][16]. The CCR5 receptor in African green monkeys [17] has been shown to be polymorphic and these polymorphisms provide some protection against SIV infection.…”