Genetically Divergent Strains of Feline Immunodeficiency Virus from the Domestic Cat ( Felis catus ) and the African Lion ( Panthera leo ) Share Usage of CD134 and CXCR4 as Entry Receptors

Abstract

The env open reading frames of African lion (Panthera leo) lentivirus (feline immunodeficiency virus [FIV Ple ]) subtypes B and E from geographically distinct regions of Africa suggest two distinct ancestries, with FIV Ple -E sharing a common ancestor with the domestic cat (Felis catus) lentivirus (FIV Fca) . Here we demonstrate that FIV Ple -E and FIV Fca share the use of CD134 (OX40) and CXCR4 as a primary receptor and coreceptor, respectively, and that both lion CD134 and CXCR4 are functional receptors for FIV Ple -E. The shared usage of CD134 and CXCR4 by FIV Fca and FIV Ple -E may have implications for in vivo cell tropism and the pathogenicity of the E subtype among free-ranging lion populations.Lentiviruses are widespread pathogens of the Felidae, infecting both domestic and nondomestic felids (5,6,10,21,40,41). In domestic cats (Felis catus), feline immunodeficiency virus (FIV Fca ) is a significant cause of disease, with infection resulting in a variable immunodeficiency syndrome characterized by recurrent gingivitis-stomatitis, cachexia, wasting, neuropathology, and an increased incidence of tumor development (1,8,9,22,26,27,37,38,52). The association between lentiviral infection and disease development in nondomestic felids is less certain, although African lions (Panthera leo) infected with the lion lentivirus FIV Ple show a dramatic decline in CD4 ϩ T lymphocytes (7, 30) and an expansion of an activated CD8 ϩ lymphocyte subpopulation expressing low levels of the CD8␣␤ heterodimer, analogous to observations of FIV (35, 45) and human immunodeficiency virus (HIV) (33) infections.FIV targets activated CD4 ϩ T lymphocytes by utilizing CD134 (OX40) as a primary attachment receptor (34) and CXCR4 as a coreceptor (43,47,51). Thus, receptor utilization is likely to be a significant contributory factor to the CD4 ϩ T lymphopenia observed in FIV-infected cats. Little is known about the receptor usage of the lentiviruses of nondomestic felids; however, the results of previous studies have indicated that the puma (Puma concolor) lentivirus FIV Pco -1695 and subtype B lion lentivirus FIV Ple -458 use alternative attachment receptors from FIV Fca (36). If neither the lion nor the puma lentiviruses use CD134 or CXCR4 as viral receptors, how then do they induce a depletion of CD4 ϩ lymphocytes? Proviral genome sequence analysis of the subtype B and E lion lentiviruses indicated that the FIV Ple -B env was most closely related to the virus of the Asiatic Pallas' cat (Felis manul) (4), whereas the FIV Ple -E env was more similar to that of the domestic cat virus FIV Fca (25) than to FIV Ple -B. These data raise the possibility of either an ancient recombinatorial event between FIV strains in the wild followed by a substantial period of divergence or a more-recent recombinatorial event with an as-yet-uncharacterized but highly divergent FIV species from lions or another lentivirus-infected African species. Here, we ask whether the phylogenetic relationship between FIV Ple -E and the domestic cat virus FIV Fca is reflec...

Putative cholesterol‐binding sites in human immunodeficiency virus (HIV) coreceptors CXCR4 and CCR5

“…The sequence alignment demonstrates that all 12 CXCR4 residues forming contacts with cholesterol are absolutely, with one exception, conserved across tetrapods including chimpanzee Pan troglodytes and sooty mangabey Cercocebus atys , which are the original sources for HIV‐1 and HIV‐2, respectively 77. Feline CXCR4, but not CCR5, is a coreceptor of FIV (feline immunodeficiency virus) from the domestic cat Felis catus 78 and African lion Panthera leo 79. We found that the 12 residues forming contacts with cholesterol in human CXCR4 are identical to the corresponding residues in CXCR4 orthologs from these two species (Supporting Information Table S1).…”

Feline Immunodeficiency Virus in South America

“…Analysis of pol gene sequence of FIV from lions ( Panthera leo ), pumas ( Puma concolor ) and domestic cats indicated that each species has a specific strain of FIV and that the strains are related but distinct [ 7 , 43 ]. Also, strains from African lions (subtype B and E) differ in their abilities to replicate in feline cell lines [ 59 ], their sensitivity to receptor antagonists [ 71 ], and their requirement for ectopic expression of CD134, the primary cellular receptor, for productive infection [ 41 ].…”

The Molecular Biology of Feline Immunodeficiency Virus (FIV)

“…Interestingly, some strains of lion FIV show a substantial divergence in structure and sequence of the envelope receptor binding domains and do not enter via CXCR4 and/or CD134 [ 35 , 36 ]. The cellular receptors for these subtype B lion FIVs have not yet been identified.…”