During Readaptation In Vivo, a Tissue Culture-Adapted Strain of Feline Immunodeficiency Virus Reverts to Broad Neutralization Resistance at Different Times in Individual Hosts but through Changes at the Same Position of the Surface Glycoprotein

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

Section: Discussionmentioning

confidence: 99%

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

Rozieres

Mathiason

Rolston

et al. 2004

“…3C). Thus, collectively, these data showed that the long-term tissue culture virus used as a vaccine had established productive infections that remained low grade and exerted no detectable clinical consequences for Ͼ4 years, exhibiting a possibly greater degree of attenuation than when the same virus had been used to inoculate cats at a lower in vitro passage (7,31,59). The virological and immunological statuses of the vaccinees at the times of challenge are detailed in Table 1.…”

Section: Low-grade Infection Established By the Vaccine Virusmentioning

confidence: 98%

AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Protection from an Intraclade Challenge Administered Systemically or Mucosally by an Attenuated Vaccine

Pistello

Matteucci

Bonci

et al. 2003

Self Cite

Feline immunodeficiency virus (FIV) infection of domestic cats represents a valuable system through which to investigate criteria for antilentiviral vaccines in a natural host species. Here, we examined whether vaccination with a strain of FIV attenuated as a result of prolonged growth in vitro could protect against a fully virulent, highly heterologous intraclade challenge. The results indicated that the vaccine virus produced a low-grade infection with no detectable pathological effects and afforded a long-lasting sterilizing immunity if the challenge was delivered intraperitoneally as cell-free virus but not against a cell-associated intravaginal challenge. In the latter case, however, the replication and pathological consequences of the challenge virus were markedly suppressed. Together with similar results obtained in rhesus monkey models, these findings should give impulse to the development of attenuated FIV vaccines to be tested in controlled studies in field cats. Field studies may provide answers to some of the existing safety concerns surrounding attenuated AIDS vaccines in humans.

“…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).…”

mentioning

confidence: 52%

“…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%

“…1). Four sera (set A) were from cats 275, 311, and 583 described in a previous report (3). These animals had been infected with 1 ml (corresponding to approximately 20 50% cat infectious doses) of supernatant of chronically infected FL4 cells (26; generous gift of Janet K. Yamamoto) on their 193rd passage (TCA FIV) and had an NS phenotype (not shown) and V4 and V5 sequences (Fig.…”

mentioning

confidence: 99%

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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...