Characterization of a Highly Pathogenic Molecular Clone of Feline Immunodeficiency Virus Clade C

Abstract

We have derived and characterized a highly pathogenic molecular isolate of feline immunodeficiency virus subtype C (FIV-C) CABCpady00C. Clone FIV-C36 was obtained by lambda cloning from cats that developed severe immunodeficiency disease when infected with CABCpady00C (Abbotsford, British Columbia, Canada). Clone FIV-C36 Env is 96% identical to the noninfectious FIV-C isolate sequence deposited in GenBank (FIV-Cgb; GenBank accession number AF474246) (A. Harmache et al.) but is much more divergent in Env when compared to the subgroup A clones Petaluma (34TF10) and FIV-PPR (76 and 78% divergence, respectively). Clone FIV-C36 was able to infect freshly isolated feline peripheral blood mononuclear cells and primary T-cell lines but failed to productively infect CrFK cells, as is typical of FIV field isolates. Two-week-old specific-pathogen-free cats infected with FIV-C36 tissue culture supernatant became PCR positive and developed severe acute immunodeficiency disease similar to that caused by the uncloned CABCpady00C parent. At 4 to 5 weeks postinfection (PI), 3 of 4 animals developed CD4+-T-cell depletion, fever, weight loss, diarrhea, and opportunistic infections, including ulcerative stomatitis and tonsillitis associated with abundant bacterial growth, pneumonia, and pyelonephritis, requiring euthanasia. Histopathology confirmed severe thymic and systemic lymphoid depletion. Interestingly, the dam also became infected with a high viral load at 5 weeks PI of the kittens and developed a similar disease syndrome, requiring euthanasia at 11 weeks PI of the kittens. This constitutes the first report of a replication-competent, infectious, and pathogenic molecular clone of FIV-C. Clone FIV-C36 will facilitate dissection of the pathogenic determinants of FIV

Sequential CD134-CXCR4 Interactions in Feline Immunodeficiency Virus (FIV): Soluble CD134 Activates FIV Env for CXCR4-Dependent Entry and Reveals a Cryptic Neutralization Epitope

“…We also tested the blocking activities of SU1-30 MAb against the Envs of two divergent primary viruses, 36C, a clade C isolate (8), and B2452, a clade B isolate (11), in standard ( Fig. 4a) and sCD134-activated (Fig.…”

Productive Replication of vif -Chimeric HIV-1 in Feline Cells

“…2A). We chose the vif allele of FIV C36 (15), an infectious molecular clone of a clade C FIV isolate (16). Prospective confidence in robust biological activity of this Vif protein was supported by evidence that FIV C36 and its parental isolate generate persistent infection with rapid progression to AIDS in 75% and 60% of domestic cats, respectively (15, 16).…”

Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

“…In most naturally infected domestic cats (Felis catus, Fca), FIV causes a severe immune deficiency only in a subpopulation of animals; however, highly pathogenic feline AIDS-inducing FIV isolates have been described (26)(27)(28)(29). Thus, FIV infections in cats are a relevant animal model for studying lentiviral AIDS induction and immune control leading to nonprogression (30)(31)(32)(33).…”

“…Primates have seven genes (A3A to A3D, A3F to A3H), whereas cats encode four genes (A3Z2a to A3Z2c, A3Z3) (3)(4)(5). A3 proteins contain either one or two zinc (Z)-binding domains with the conserved motif of HxE(x) [23][24][25][26][27][28] CxxC (where "x" can be any residue) (4). These proteins can target retroviruses and inhibit viral replication by deamination of cytidines in viral single-strand DNA that forms during reverse transcription, introducing G-to-A hypermutations in the coding strand (6)(7)(8)(9)(10).…”