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

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.

Feline Immunodeficiency Virus Cross-Species Transmission: Implications for Emergence of New Lentiviral Infections

“…PLVA proviral loads in bobcats and PLVB proviral loads in mountain lions were significantly higher than PLVA proviral loads in mountain lions. PLVB proviral loads in mountain lions were significantly higher than PLVA proviral loads in bobcats, though viral copy numbers in both species were within a range similar to those reported for host-adapted subtypes of FIV in domestic cats (ϳ10 3 to 10 4 proviral copies/10 6 cells) (46)(47)(48). Our inability to quantitate PLVA provirus from a number of animals that were positive by conventional PCR is likely a reflection of low proviral loads and potentially reflects partial degradation of some archival samples.…”

Novel Gammaherpesviruses in North American Domestic Cats, Bobcats, and Pumas: Identification, Prevalence, and Risk Factors

“…Archived blood cell DNA from specific-pathogen-free domestic cats was obtained from three previous studies (22)(23)(24). BoHV4 and feline herpesvirus 1 (FeHV1) DNAs were extracted from infected cell culture supernatants (provided by Hana Van Campen and Sandra Quackenbush, respectively, both of Colorado State University) using a QIAamp DNA blood kit (Qiagen).…”

Accessory Genes Confer a High Replication Rate to Virulent Feline Immunodeficiency Virus

“…FIV-PCenv, a chimera containing the 3= half of HV-FIV, including vif, orfA, rev1, and env, on the LV-FIV background demonstrated intermediate, although delayed, viral loads and hematological pathology during primary infection of cats (47). Passage of FIV-PCenv from infected cats into naive cats resulted in higher viral loads, similar to those observed during parental HV-FIV infections, which are not delayed compared to the infection kinetics of parental constructs (48). Thus, the results from experiments with subtype A/C chimeric FIV-PCenv suggest that elements from the 3= half of the genome, including the accessory genes vif and orfA, contribute to the heightened virulence observed during infections with the HV-FIV strain.…”

“…However, the specific viral characteristics associated with pathogenicity remain relatively poorly understood. FIV infection of the domestic cat offers a model system for research on lentiviral pathogenesis in an authentic host species with a disease pathology highly similar to that of HIV/ AIDS, since one of the best-characterized features of the FIV system is the exhaustive documentation of strain-specific pathologies associated with genetically divergent FIV strains (5,17,(43)(44)(45)(46)(47)(48). Therefore, studies on the viral genetic basis for FIV pathogenicity can inform our understanding of other lentiviruses, such as HIV, by examining important genetic elements which lentiviruses share, such as Vif.…”

“…1; for Multicycle replication of chimeric viruses has the potential to result in the selection of adaptive mutations within or surrounding the chimeric region. We have previously observed this phenomenon in the integrase-encoding portion of pol in the FIVPCenv chimera (48). To determine whether any mutations were selected for in our chimeric virus production and subsequent replication in Mya-1 cells, we sequenced viral RNA from the day 15 supernatants of Mya-1 cell infections, whose replication kinetics are shown in Figure 2.…”