Pathogenicity and Rapid Growth Kinetics of Feline Immunodeficiency Virus Are Linked to 3′ Elements

Jesse Thompson,John H Elder,Charles Wood,Martha Macmillan,Sue Vandewoude,Karen Boegler

doi:10.1371/journal.pone.0024020

Abstract

Chimeric viruses constructed between a highly pathogenic Feline Immunodeficiency Virus isolate (FIV-C36) and a less pathogenic but neurotropic strain (FIV-PPR) have been used to map viral genetic determinants of in vivo pathogenicity. Chimeric virus FIV-PCenv, which contains FIV-C36 genome from the 3′ region of pol to upstream of the 3′LTR on an FIV-PPR backbone, was previously shown to be replication-competent in vivo, inducing altered CD4+ T-cell and neutrophil profiles intermediate between parental strains following a delay in viral replication during initial infection. Examination of FIV-PCenv proviral sequences recovered at week 11 post-infection revealed two changes compared to initial viral inoculum; the most significant being arginine to histidine in the integrase region of Pol at residue 813 (R813H). Pooled plasma from the initial in vivo study was used to inoculate a second cohort of cats to determine whether similar virulence and kinetics could be established following primary infection. Viral replication kinetics and immunocyte profiles were monitored in blood, bone marrow, and saliva over a one-year period. Passaged FIV-PCenv again displayed intermediate phenotype between parental strains, but unlike primary experiments, the onset of acute viremia was not delayed. CD4/8 alterations were noted in all groups of animals, though significant changes from controls were delayed in FIV-PPR infected animals compared to FIV-C36 and FIV-PCenv. In vivo passage of FIV-PCenv increased replication-competence relative to the initial molecularly-cloned chimera in association with one adaptive nucleotide change in the 5′ end of the genome relative to primary tissue culture inoculum, while mutations in the 3′ end of the genome were not detected. The results are consistent with the interpretation that 3′ elements contribute to heightened virulence of FIV-C36, and that integrase residue 813 plays an important role in facilitating successful in vivo replication.

Highlights

Feline immunodeficiency virus (FIV) is a naturally-occurring lentivirus of domestic cats
Pathology of lentivirus subtypes can be attributed to any number of properties, including replication rates or levels dictated by a combination of viral and host factors; these include viral genome secondary structure, efficacy of evasion of a host innate or adaptive immune response, binding affinity to cell surface receptors, and epigenetic factors
Despite equivalent challenge doses [24]. These findings suggested that (1) FIV-C36 genomic elements represented in FIV-PCenv are related to pathogenicity, and (2) infection with primary FIVPCenv may have resulted in accumulation of mutations leading to enhanced replication capacity following an initial delay

Summary

Introduction

Feline immunodeficiency virus (FIV) is a naturally-occurring lentivirus of domestic cats. FIV has a similar genome structure as human immunodeficiency virus (HIV) [7], containing several open-reading-frame (ORF) accessory genes [8,9], and uses a two-receptor mechanism, with cellular entry via CXCR4 chemokine receptor [10,11,12,13]. Similarities between these complex lentiviruses make FIV infections a relevant animal model for studies of HIV-AIDS [14,15]. Several chimeric constructs were developed by exchanging elements between FIV-C36 and FIV-PPR as previously reported and reviewed in Figure 1 [24]

Methods

Results

Conclusion