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Journal of Virology, August 2008, p. 7953-7963, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00337-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Replication Properties of Clade A/C Chimeric Feline Immunodeficiency Viruses and Evaluation of Infection Kinetics in the Domestic Cat{triangledown}

Sohela de Rozìeres,1,{dagger},{ddagger} Jesse Thompson,2,{ddagger} Magnus Sundstrom,1 Julia Gruber,2 Debora S. Stump,2 Aymeric P. de Parseval,1 Sue VandeWoude,2 and John H. Elder1*

Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037,1 Department of Pathology, College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado 805232

Received 15 February 2008/ Accepted 5 June 2008

Feline immunodeficiency virus (FIV) causes progressive immunodeficiency in domestic cats, with clinical course dependent on virus strain. For example, clade A FIV-PPR is predominantly neurotropic and causes a mild disease in the periphery, whereas clade C FIV-C36 causes fulminant disease with CD4+ T-cell depletion and neutropenia but no significant pathology in the central nervous system. In order to map pathogenic determinants, chimeric viruses were prepared between FIV-C36 and FIV-PPR, with reciprocal exchanges involving (i) the 3' halves of the viruses, including the Vif, OrfA, and Env genes; (ii) the 5' end extending from the 5' long terminal repeat (LTR) to the beginning of the capsid (CA)-coding region; and (iii) the 3' LTR and Rev2-coding regions. Ex vivo replication rates and in vivo replication and pathologies were then assessed and compared to those of the parental viruses. The results show that FIV-C36 replicates ex vivo and in vivo to levels approximately 20-fold greater than those of FIV-PPR. None of the chimeric FIVs recapitulated the replication rate of FIV-C36, although most replicated to levels similar to those of FIV-PPR. The rates of chloramphenicol acetyltransferase gene transcription driven by the FIV-C36 and FIV-PPR LTRs were identical. Furthermore, the ratios of surface glycoprotein (SU) to capsid protein (CA) in the released particles were essentially the same in the wild-type and chimeric FIVs. Tests were performed in vivo on the wild-type FIVs and chimeras carrying the 3' half of FIV-C36 or the 3' LTR and Rev2 regions of FIV-C36 on the PPR background. Both chimeras were infectious in vivo, although replication levels were lower than for the parental viruses. The chimera carrying the 3' half of FIV-C36 demonstrated an intermediate disease course with a delayed peak viral load but ultimately resulted in significant reductions in neutrophil and CD4+ T cells, suggesting potential adaptation in vivo. Taken together, the findings suggest that the rapid-growth phenotype and pathogenicity of FIV-C36 are the result of evolutionary fine tuning throughout the viral genome, rather than being properties of any one constituent.

* Corresponding author. Mailing address: The Scripps Research Institute, 10550 N. Torrey Pines Road, MB-14, La Jolla, CA 92037. Phone: (858) 784-8270. Fax: (858) 784-2750. E-mail: jelder{at}scripps.edu

{triangledown} Published ahead of print on 11 June 2008.

{dagger} Present address: Biomatrica, Inc., 5627 Oberlin Dr., Ste. 124, San Diego, CA 92121.

{ddagger} Co-first authors.

Journal of Virology, August 2008, p. 7953-7963, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00337-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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