<b>Sequence Note</b>: Reduced Sensitivity to Strain-Specific Neutralization of Laboratory-Adapted Feline Immunodeficiency Virus after One Passage in Vivo: Association with Amino Acid Substitutions in the V4 Region of the Surface Glycoprotein

The development of an effective vaccine against human immunodeficiency virus is considered to be the most practicable means of controlling the advancing global AIDS epidemic. Studies with the domestic cat have demonstrated that vaccinal immunity to infection can be induced against feline immunodeficiency virus (FIV); however, protection is largely restricted to laboratory strains of FIV and does not extend to primary strains of the virus. We compared the pathogenicity of two prototypic vaccine challenge strains of FIV derived from molecular clones; the laboratory strain PET F14 and the primary strain GL8 414 . PET F14 established a low viral load and had no effect on CD4؉ -or CD8 ؉ -lymphocyte subsets. In contrast, GL8 414 established a high viral load and induced a significant reduction in the ratio of CD4؉ to CD8 ؉ lymphocytes by 15 weeks postinfection, suggesting that PET F14 may be a low-virulence-challenge virus. However, during long-term monitoring of the PET F14 -infected cats, we observed the emergence of variant viruses in two of three cats. Concomitant with the appearance of the variant viruses, designated 627 W135 and 628 W135, we observed an expansion of CD8 ؉ -lymphocyte subpopulations expressing reduced CD8 ␤-chain, a phenotype consistent with activation. The variant viruses both carried mutations that reduced the net charge of the V3 loop (K409Q and K409E), giving rise to a reduced ability of the Env proteins to both induce fusion and to establish productive infection in CXCR4-expressing cells. Further, following subsequent challenge of naïve cats with the mutant viruses, the viruses established higher viral loads and induced more marked alterations in CD8؉ -lymphocyte subpopulations than did the parent F14 strain of virus, suggesting that the E409K mutation in the PET F14 strain contributes to the attenuation of the virus.

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Evolution of Replication Efficiency following Infection with a Molecularly Cloned Feline Immunodeficiency Virus of Low Virulence

Hosie

Willett

Klein

et al. 2002

“…In particular, the neutralization properties of FIV closely resemble those of HIV-1, including that TCA strains are readily inhibited by immune sera in vitro whereas fresh isolates exhibit a generalized resistance to antibody-mediated neutralization (1,9). In previous studies, we observed that, upon reinoculation into cats, an exquisitely NS laboratory TCA strain of FIV regained the broadly neutralization-resistant (NR) phenotype typical of wild-type viruses (3,6). This closely mimicked what also observed with TCA strains of HIV and chimeric simian-HIV following in vivo readaption (2,7).…”

supporting

confidence: 66%

“…In previous studies (3,6), the force(s) that had selected in favor of the reversion to broad neutralization resistance which occurred when an NS TCA strain of FIV was readapted to cats had remained undefined. Here, we looked at the issue by exposing the same virus to selection in vitro by four immune sera obtained from three cats in which the NS3NR reversion had recently taken place.…”

Section: Discussionmentioning

confidence: 99%

Feline Immunodeficiency Virus-Infected Cat Sera Associated with the Development of Broad Neutralization Resistance In Vivo Drive Similar Reversions In Vitro

Giannecchini

Matteucci

Ferrari

et al. 2001

Self Cite

We previously reported that, upon reinoculation into cats, a neutralization-sensitive, tissue culture-adapted strain of feline immunodeficiency virus constantly reverted to the broad neutralization resistance typical of primary virus isolates and identified residue 481 in the V4 region of the surface glycoprotein as a key determinant of the reversion. Here, we found that well-characterized immune sera, obtained from cats in which such reversion had occurred, selected in tissue culture in favor of virus variants that also had a neutralizationresistant phenotype and had amino acid 481 changed, thus indicating that the host's humoral immune response is capable of driving the reversion in the absence of other intervening factors. In contrast, a second group of immune sera, elicited by a virus variant that had already reverted to neutralization resistance in independent cats, induced the emergence of escape mutants lacking broad neutralization resistance and neutralized fewer virus variants. It is proposed that the viral variants used to produce the two sets of sera may have generated different antibody repertoires.Naturally occurring lentiviruses are only occasionally inhibited by sera of infected subjects in in vitro neutralization assays, and this property is currently the focus of intensive investigation since it is considered instrumental for virus persistence and pathogenicity as well as a formidable obstacle in the development of effective prophylactic vaccines (5, 16). With regard to the latter point, several immunogens have indeed been shown to protect against neutralization-sensitive (NS), tissue culture-adapted (TCA) laboratory lentiviruses but not against isolates recently cultured from infected hosts (11,25). In spite of considerable recent advances on the structural features that permit wild-type lentiviruses to resist potentially neutralizing antibodies (7,8,13,15,20,27), what determines conservation of this important viral attribute of wild-type lentiviruses is poorly understood. In fact, although it seems feasible that continued exposure to antiviral antibody is important (4), this has never been formally demonstrated. In principle, alternative or adjunctive intervening factors include other innate and adaptive immune effectors and the need to conserve the usage of certain receptor-coreceptor systems which determine virus tropism for specific cell types (17).Feline immunodeficiency virus (FIV) is an important pathogen of domestic cats and, due to extensive similarities with human immunodeficiency virus type 1 (HIV-1), is a valuable model for AIDS studies (10,18,24). In particular, the neutralization properties of FIV closely resemble those of HIV-1, including that TCA strains are readily inhibited by immune sera in vitro whereas fresh isolates exhibit a generalized resistance to antibody-mediated neutralization (1, 9). In previous studies, we observed that, upon reinoculation into cats, an exquisitely NS laboratory TCA strain of FIV regained the broadly neutralization-resistant (NR) phenotype typical...

“…However, when compared to clade A and B Env proteins, the identity is only 78 and 76%, respectively. Predictably, the biggest diversity is located in regions V3 to V5 (2,3,40). The V3-V4 region was shown to contain macrophage-tropic determinants, whereas a loss in positively charged residues in V3 may allow a T-cell-tropic phenotype (49).…”

Section: Discussionmentioning

confidence: 99%

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

Rozieres

Mathiason

Rolston

et al. 2004

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