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Journal of Virology, May 2001, p. 4584-4593, Vol. 75, No. 10
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.10.4584-4593.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

During Readaptation In Vivo, a Tissue Culture-Adapted Strain of Feline Immunodeficiency Virus Reverts to Broad Neutralization Resistance at Different Times in Individual Hosts but through Changes at the Same Position of the Surface Glycoprotein

Mauro Bendinelli,1,* Mauro Pistello,1 Daniela Del Mauro,1 Giancarlo Cammarota,1 Fabrizio Maggi,1 Alessandro Leonildi,1 Simone Giannecchini,1 Carlo Bergamini,2 and Donatella Matteucci1

Retrovirus Center and Virology Section, Department of Biomedicine, University of Pisa, Pisa,1 and Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara,2 Italy

Received 8 November 2000/Accepted 21 February 2001

The broad resistance to antibody-mediated neutralization of lentiviruses recently isolated from infected hosts is a poorly understood feature which might contribute to the ability of these viruses to persist and to the failure of experimental vaccines to protect against virulent viruses. We studied the underlying molecular mechanisms by examining the evolution of a neutralization-sensitive, tissue culture-adapted strain of feline immunodeficiency virus upon reinoculation into specific-pathogen-free cats. Reversion to broad neutralization resistance was observed in seven of seven inoculated animals and, in individual hosts, started to develop between less than 4 and more than 15 months from infection. After comparison of the envelope sequences of the inoculum virus, of an additional 4 neutralization-sensitive in vitro variants, and of 14 ex vivo-derived variants (6 neutralization sensitive, 5 resistant, and 3 with intermediate phenotype), a Lysright-arrowAsn or right-arrowGlu change at position 481 in the V4 region of the surface glycoprotein appeared as a key player in the reversion. This conclusion was confirmed by mutagenesis of molecularly cloned virus. Analysis of viral quasispecies and biological clones showed that the intermediate phenotype was due to transient coexistence of neutralization-sensitive and -resistant variants. Since the amino acid position involved was the same in four of four recent revertants, it is suggested that the number of residues that control reversion to broad neutralization resistance in FIV might be very limited. Amino acid 481 was found to be changed only in one of three putative long-term revertants. These variants shared a Serright-arrowAsn change at position 557 in region V5, which probably collaborated with other mutations in long-term maintenance of neutralization resistance, as suggested by the study of mutagenized virus.

* Corresponding author. Mailing address: Dipartimento di Biomedicina, Università di Pisa, Via San Zeno 37, I-56127 Pisa, Italy. Phone: 39 (050) 553 562. Fax: 39 (050) 559 455. E-mail: bendinelli{at}biomed.unipi.it.

Journal of Virology, May 2001, p. 4584-4593, Vol. 75, No. 10
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.10.4584-4593.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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