During readaptation in vivo, a tissue culture-adapted strain of feline immunodeficiency virus reverts to broad neutralization resistance at differenttimes in individual hosts but through changes at the same position of the surface glycoprotein

The broad resistance to antibody-mediated neutralization of lentiviruses re cently isolated from infected hosts is a poorly understood feature which mi ght contribute to the ability of these viruses to persist and to the failur e of experimental vaccines to protect against virulent viruses. We studied the underlying molecular mechanisms by examining the evolution of a neutral ization-sensitive, tissue culture-adapted strain of feline immunodeficiency virus upon reinoculation into specific-pathogen-free cats. Reversion to br oad neutralization resistance was observed in seven of seven inoculated ani mals and, in individual hosts, started to develop between less than 4 and m ore than 15 months from infection. After comparison of the envelope sequenc es of the inoculum virus, of an additional 4 neutralization-sensitive In vi tro variants, and of 14 ex vivo derived variants (6 neutralization sensitiv e, 5 resistant, and 3 with intermediate phenotype), a Lys --> Asn or --> Gl u change at position 481 in the V4 region of the surface glycoprotein appea red as a key player in the reversion, This conclusion was confirmed by muta genesis of molecularly cloned virus. Analysis of viral quasispecies and bio logical 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 bro ad neutralization resistance in FIV might be very limited. Amino acid 481 w as found to be changed only in one of three putative long-term revertants. These variants shared a Ser --> Asn change at position 557 in region V5, wh ich probably collaborated with other mutations in long-term maintenance of neutralization resistance, as suggested by the study of mutagenized virus.