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.
Highlights
Feline immunodeficiency virus (FIV) targets CD4+ helper T cells by an initial high affinity interaction between the viral envelope glycoprotein and CD134 (OX40) [1,2] and a subsequent interaction with the chemokine receptor CXCR4 [3,4]
Infection of both groups led to a significant reduction in the CD4:CD8 ratio compared with age-matched controls (Fig. 1), there was no significant difference in CD4:CD8 ratios between the two groups at each of the time points that were compared
While infection with the clonal virus appeared to induce a transient increase in CD8+ lymphocytes and significant reduction in CD4+ lymphocytes, infection with the mixture of viral variants induced a sustained increase in CD8+ lymphocytes and a more modest reduction in CD4+ lymphocytes
Summary
Feline immunodeficiency virus (FIV) targets CD4+ helper T cells by an initial high affinity interaction between the viral envelope glycoprotein and CD134 (OX40) [1,2] and a subsequent interaction with the chemokine receptor CXCR4 [3,4]. As expression of CD134 is restricted to activated CD4+ (not CD8+) T cells, FIV infection of the domestic cat results in an immune dysfunction characterised by a progressive depletion of helper T cells. Infection with a cell culture-adapted strain of virus results in an inapparent infection with low viral loads and stable CD4+ T cell numbers [5]. Infection with a primary isolate of virus, serially passaged in vivo during the acute phase of infection, results in the development of a disease state characterised by a high viral load, precipitous decline in CD4+ T cell numbers, lymphoid depletion and susceptibility to opportunistic infections [6]. The pathogenicity of different strains of FIV may be influenced by both host and viral factors, for example variants bearing mutations in the FIV orfA gene are defective for growth in primary T cells [7,8,9] while the viral Vif protein permits evasion of the antiviral activities of host APOBEC proteins [10]
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