Selective Expansion of Viral Variants following Experimental Transmission of a Reconstituted Feline Immunodeficiency Virus Quasispecies

Abstract

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development.

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

“…The selective pressure for the emergence of CRD2-independent viruses may be escape from humoral or cellular immunity, with the accrued mutations in Env impacting on the virus-receptor interaction [ 30 , 32 ]. Consistent with this hypothesis, when cats were challenged with a reconstituted viral quasispecies containing equal titres of clonal variants with either CRD2-dependent or CRD2-independent Envs (early and late phenotypes), the CRD2-dependent viruses expanded preferentially in vivo while the CRD2-independent viruses failed to thrive [ 33 ].…”

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

“…These CRD2-independent isolates, which are characteristic of the later stages of FIV infection, were also shown to be less efficient for transmission and replication during acute infection when compared to CRD2-dependent isolates in experimental infection studies. These findings generated a hypothesis that CRD2-dependent FIV isolates, which are efficiently transmitted in vivo and able to achieve higher virus loads during early infection, may be analogous to CCR5-dependent HIV-1 isolates that also transmit much more efficiently during primary HIV-1 infection of humans when compared to later-emerging CXCR4-tropic variants in HIV-1 infection [49,50]. Specific CD4+ T cell subsets that may be specific targets for these CRD2-dependent FIV isolates and their role in viral pathogenesis remain to be determined.…”

The Comparative Value of Feline Virology Research: Can Findings from the Feline Lentiviral Vaccine Be Translated to Humans?

“…This hypothesis was supported by the findings from a study conducted in cats experimentally inoculated with reconstituted quasispecies composed of GL8 and variants containing CRD2-dependent or CRD2-independent Envs [ 44 ]. Throughout the 21-week period of study, the variants of GL8 containing CRD2-dependent Envs replicated faster and selectively expanded in all cats.…”

“…Throughout the 21-week period of study, the variants of GL8 containing CRD2-dependent Envs replicated faster and selectively expanded in all cats. It was demonstrated that the failure to replicate by the CRD2-independent variants was not associated with either the presence of neutralising antibodies or cell-mediated immune responses [ 44 ], suggesting that the switch in receptor phenotype also led to decreased replicative fitness.…”