Mapping the domains of CD134 as a functional receptor for feline immunodeficiency virus (FIV)

The feline homologue of CD134 (fCD134) is the primary binding receptor for feline immunodeficiency virus (FIV), targeting the virus preferentially to activated CD4+ helper T cells. However, strains of FIV differ in their utilisation of CD134; the prototypic strain PPR, requires a minimal determinant in CRD1 of fCD134 to confer near optimal receptor function while strains such as GL8 require additional determinants in the CD134 CRD2. We map this determinant to a loop in CRD2 governing the interaction between the receptor and its ligand; substitution of amino acids S78N,S79Y,K80E restored full viral receptor activity to the CDR2 of human CD134 in the context of feline CD134 with tyrosine-79 appearing to be the critical residue for restoration of receptor function

Mapping the domains of CD134 as a functional receptor for feline immunodeficiency virus (FIV)

The feline homologue of CD134 (fCD134) is the primary binding receptor for feline immunodeficiency virus (FIV), targeting the virus preferentially to activated CD4+ helper T cells. However, strains of FIV differ in their utilisation of CD134; the prototypic strain PPR, requires a minimal determinant in CRD1 of fCD134 to confer near optimal receptor function while strains such as GL8 require additional determinants in the CD134 CRD2. We map this determinant to a loop in CRD2 governing the interaction between the receptor and its ligand; substitution of amino acids S78N,S79Y,K80E restored full viral receptor activity to the CDR2 of human CD134 in the context of feline CD134 with tyrosine-79 appearing to be the critical residue for restoration of receptor function

The comparative value of feline virology research: can findings from the feline lentiviral vaccine be translated to humans?

Feline immunodeficiency virus (FIV) is a lentivirus of domestic cats that shares several similarities with its human counterpart, human immunodeficiency virus (HIV). Their analogies include genomic organization, lymphocyte tropism, viral persistence and induction of immunodeficiency. FIV is the only lentivirus for which a commercial vaccine is registered for prevention in either human or veterinary medicine. This provides a unique opportunity to investigate the mechanisms of protection induced by lentivirus vaccines at the population level and might contribute to the development of efficacious HIV vaccines. As well as having comparative value for vaccine studies, FIV research has shed some light on the relationship between lentiviral tropism and pathogenesis. Recent studies in our laboratory demonstrated that the interaction between FIV and its primary receptor changes as disease progresses, reminiscent of the receptor switch observed as disease progresses in HIV infected individuals. Here we summarise findings illustrating that, in addition to its veterinary significance, FIV has comparative value, providing a useful model to explore lentivirus–host interactions and to examine potential immune correlates of protection against HIV infection

Anger, Quality of Life and Mood in Multiple Sclerosis

This research was funded by The Multiple Sclerosis Society (UK).Peer reviewedPublisher PD

Rapid evolution of the env gene leader sequence in cats naturally infected with feline immunodeficiency virus (FIV)

Analysing the evolution of FIV on the intra-host level is important, in order to address whether the diversity and composition of viral quasispecies affects disease progression.<p></p> We examined the intra-host diversity and the evolutionary rates of the entire env and structural fragments of the env sequences obtained from sequential blood samples in 43 naturally infected domestic cats that displayed different clinical outcomes. We observed in the majority of cats that FIV env showed very low levels of intra-host diversity. We estimated that env evolved at the rate of 1.16 x 10-3 substitutions per site per year and demonstrated that recombinant sequences evolved faster than non-recombinant sequences. It was evident that the V3-V5 fragment of FIV env displayed higher evolutionary rates in healthy cats than in those with terminal illness. Our study provided the first evidence that the leader sequence of env, rather than the V3-V5 sequence, had the highest intra-host diversity and the highest evolutionary rate of all env fragments, consistent with this region being under a strong selective pressure for genetic variation.<p></p> Overall, FIV env displayed relatively low intra-host diversity and evolved slowly in naturally infected cats. The maximal evolutionary rate was observed in the leader sequence of env. Although genetic stability is not necessarily a prerequisite for clinical stability, the higher genetic stability of FIV compared to HIV might explain why many naturally infected cats do not progress to AIDS rapidly.<p></p&gt

Neutralising antibody response in domestic cats immunised with a commercial feline immunodeficiency virus (FIV) vaccine

Across human and veterinary medicine, vaccines against only two retroviral infections have been brought to market successfully, the vaccines against feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV). FeLV vaccines have been a global success story, reducing virus prevalence in countries where uptake is high. In contrast, the more recent FIV vaccine was introduced in 2002 and the degree of protection afforded in the field remains to be established. However, given the similarities between FIV and HIV, field studies of FIV vaccine efficacy are likely to advise and inform the development of future approaches to HIV vaccination.<p></p> Here we assessed the neutralising antibody response induced by FIV vaccination against a panel of FIV isolates, by testing blood samples collected from client-owned vaccinated Australian cats. We examined the molecular and phenotypic properties of 24 envs isolated from one vaccinated cat that we speculated might have become infected following natural exposure to FIV. Cats vaccinated against FIV did not display broadly neutralising antibodies, suggesting that protection may not extend to some virulent recombinant strains of FIV circulating in Australia.<p></p&gt

Duration of antibody response following vaccination against feline immunodeficiency virus

Objectives: Recently, two point-of-care (PoC) feline immunodeficiency virus (FIV) antibody test kits (Witness and Anigen Rapid) were reported as being able to differentiate FIV-vaccinated from FIV-infected cats at a single time point, irrespective of the gap between testing and last vaccination (0–7 years). The aim of the current study was to investigate systematically anti-FIV antibody production over time in response to the recommended primary FIV vaccination series. Methods: First, residual plasma from the original study was tested using a laboratory-based ELISA to determine whether negative results with PoC testing were due to reduced as opposed to absent antibodies to gp40. Second, a prospective study was performed using immunologically naive client-owned kittens and cats given a primary FIV vaccination series using a commercially available inactivated whole cell/inactivated whole virus vaccine (Fel-O-Vax FIV, three subcutaneous injections at 4 week intervals) and tested systematically (up to 11 times) over 6 months, using four commercially available PoC FIV antibody kits (SNAP FIV/FeLV Combo [detects antibodies to p15/p24], Witness FeLV/FIV [gp40], Anigen Rapid FIV/FeLV [p24/gp40] and VetScan FeLV/FIV Rapid [p24]). Results: The laboratory-based ELISA showed cats from the original study vaccinated within the previous 0–15 months had detectable levels of antibodies to gp40, despite testing negative with two kits that use gp40 as a capture antigen (Witness and Anigen Rapid kits). The prospective study showed that antibody testing with SNAP Combo and VetScan Rapid was positive in all cats 2 weeks after the second primary FIV vaccination, and remained positive for the duration of the study (12/12 and 10/12 cats positive, respectively). Antibody testing with Witness and Anigen Rapid was also positive in a high proportion of cats 2 weeks after the second primary FIV vaccination (8/12 and 7/12, respectively), but antibody levels declined below the level of detection in most cats (10/12) by 1 month after the third (final) primary FIV vaccination. All cats tested negative using Witness and Anigen Rapid 6 months after the third primary FIV vaccination. Conclusions and relevance: This study has shown that a primary course of FIV vaccination does not interfere with FIV antibody testing in cats using Witness and Anigen Rapid, provided primary vaccination has not occurred within the previous 6 months. Consequently, Witness and Anigen Rapid antibody test kits can be used reliably to determine FIV infection status at the time of annual booster FIV vaccination to help detect ‘vaccine breakthroughs’ and in cats that have not received a primary course of FIV vaccination within the preceding 6 months. The duration of antibody response following annual booster FIV vaccination and the resulting effect on antibody testing using PoC kits needs to be determined by further research. The mechanism(s) for the variation in FIV antibody test kit performance remains unclear

Evolution of replication efficiency following infection with a molecularly cloned feline immunodeficiency virus of low virulence

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<sub>F14</sub> and the primary strain GL8<sub>414</sub>. PET<sub>F14</sub> established a low viral load and had no effect on CD4<sup>+</sup>- or CD8<sup>+</sup>- lymphocyte subsets. In contrast, GL8<sub>414</sub> established a high viral load and induced a significant reduction in the ratio of CD4<sup>+</sup> to CD8<sup>+</sup> lymphocytes by 15 weeks postinfection, suggesting that PET<sub>F14</sub> may be a low-virulence-challenge virus. However, during long-term monitoring of the PET<sub>F14</sub>-infected cats, we observed the emergence of variant viruses in two of three cats. Concomitant with the appearance of the variant viruses, designated 627<sub>W135</sub> and 628<sub>W135</sub>, we observed an expansion of CD8<sup>+</sup>-lymphocyte subpopulations expressing reduced CD8 ß-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<sup>+</sup>-lymphocyte subpopulations than did the parent F14 strain of virus, suggesting that the E409K mutation in the PET<sub>F14</sub> strain contributes to the attenuation of the virus

Truncation of TRIM5 in the <i>Feliformia</i> explains the absence of retroviral restriction in cells of the domestic cat

TRIM5[alpha] mediates a potent retroviral restriction phenotype in diverse mammalian species. Here, we identify a TRIM5 transcript in cat cells with a truncated B30.2 capsid binding domain and ablated restrictive function which, remarkably, is conserved across the &lt;i&gt;Feliformia&lt;/i&gt;. Cat TRIM5 displayed no restriction activity, but ectopic expression conferred a dominant negative effect against human TRIM5[alpha]. Our findings explain the absence of retroviral restriction in cat cells and suggest that disruption of the TRIM5 locus has arisen independently at least twice in the &lt;i&gt;Carnivora&lt;/i&gt;, with implications concerning the evolution of the host and pathogen in this taxon