An investigation of the breadth of neutralising antibody response in cats naturally infected with feline immunodeficiency virus

Neutralising antibodies (NAbs) are believed to comprise an essential component of the protective immune response induced by vaccines against FIV and HIV infections. However, relatively little is known about the role of NAbs in controlling FIV infection and subsequent disease progression. Here we present studies examining the neutralisation of HIV-luciferase pseudotypes bearing homologous and heterologous FIV Envs (n=278) by sequential plasma samples collected at 6 month intervals from naturally infected cats (n=38) over a period of 18 months. We evaluated the breadth of the NAb response against non-recombinant homologous and heterologous clade A and clade B viral variants as well as recombinants and assessed the results, testing for evidence of an association between the potency of the NAb response and the duration of infection, CD4 T lymphocyte numbers, health status and survival times of the infected cats. Neutralisation profiles varied significantly between FIV infected cats and strong autologous neutralisation, assessed using luciferase based in vitro assays, did not correlate with the clinical outcome. No association was observed between strong NAb responses and either improved health status or increased survival time of infected animals, implying that other protective mechanisms are likely to be involved. Similarly, no correlation was observed between the development of autologous NAbs and the duration of infection. Furthermore, cross-neutralising antibodies were evident in only a small proportion (13%) of cats

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

Emergence of CD134 cysteine-rich domain 2 (CRD2)-independent strains of feline immunodeficiency virus (FIV) is associated with disease progression in naturally infected cats

<b>Background</b> Feline immunodeficiency virus (FIV) infection is mediated by sequential interactions with CD134 and CXCR4. Field strains of virus vary in their dependence on cysteine-rich domain 2 (CRD2) of CD134 for infection.<p></p> <b>Findings</b> Here, we analyse the receptor usage of viral variants in the blood of 39 naturally infected cats, revealing that CRD2-dependent viral variants dominate in early infection, evolving towards CRD2-independence with disease progression.<p></p> <b>Conclusions</b> These findings are consistent with a shift in CRD2 of CD134 usage with disease progression.<p></p&gt

Host and Viral Determinants of Feline Immunodeficiency Virus Pathogenicity

Background Infection with feline immunodeficiency virus (FIV) is mediated by attachment to CD134 (OX40) followed by a second interaction with CXCR4, the sole co-receptor for infection. However, the in vivo cell tropism of FIV expands with time post-infection, analogous to the shift in cell tropism observed with HIV-1 as co-receptor usage switches from CCR5 to CXCR4. Here, we ask whether alterations in the Env-CD134 interaction underpin the shift in FIV cell tropism and whether this is associated with disease progression. Results Experimental transmission of a reconstituted quasispecies comprising viral variants with distinct modes of interaction with CD134 [1,2] revealed the selective expansion of variants bearing Envs typical of “early”, acute infection, binding CD134 through determinants in both cysteine rich domains (CRDs) 1 and 2. In contrast, variants with Envs typical of “late”, chronic infection (binding via CRD1 only) failed to thrive following experimental transmission. The basis for the defective replication of “late” variants did not lie in suppression by the humoral or cellular immune responses, but correlated with the nature of the virus-receptor interaction. In order to assess whether our experimental observations on CD134 usage extended to natural infection of free-ranging cats, we characterized the receptor usage of viruses from two groups of cats naturally infected with FIV (n=44). Cats displaying clinical signs were more likely to harbour viral variants with a “late” phenotype (CRD1-dependent) than healthy cats. The emergence of CRD1-dependent variants coincided with declining health status, lower CD4 lymphocyte counts and led to shorter survival times. However, it was apparent that the shift from a CRD1&2 to CRD1-dependent interaction with CD134 was not a prerequisite for disease progression, as 25% of the cats that died during the study did not harbour Env variants displaying the “late” phenotype. Conclusions The shift in CD134 usage observed following natural infection with FIV aligns with a model whereby transmitted viruses switch from CRD1&2-dependent binding to CD134, to a CRD1-dependent interaction as disease progresses. Whether this shift in receptor usage is a cause or consequence of disease progression remains to be established, however, receptor usage may serve as a prognostic indicator for disease progression