Antigenic variation is a characteristic feature of lentiviral infection. The SIV/macaque model of AIDS provides an ideal system in which to investigate the molecular basis of antigenic variation. The purpose of this study was to genetically map the nucleotide changes in env that alter the neutralization phenotype of SIV. Serum taken from an SIV(mac)239- infected macaque (2D) at 30 weeks postinoculation was found to neutralize the input virus (SIV(mac)239) and an isolate, P9, obtained at 10 weeks p.i., but did not neutralize two other isolates, P13 and P23, obtained at 20 and 52 weeks, respectively. Sequence analysis of these virus variants revealed clustered amino acid changes in V1 and single base pair changes in V2-V4 of P13 and P23. Infectious recombinant viruses in which the V1 and V1-V3 sequences of SIV(mac)239 were replaced with those of P13 or P23 retained the neutralization profile of SIV(mac)239; both were neutralized by macaque 2D serum. Recombinants containing the entire surface glycoprotein (gp120) (V1- V5) and the 5' portion of gp41 of P13 and P23 and those containing gp120 sequences from V4 through the 5' portion of the transmembrane glycoprotein (gp41) were not neutralized by 2D serum. Using a panel of monoclonal antibodies in radioimmunoprecipitation assays, P23 and recombinants containing V4 and V5 of P23 were shown to be antigenically distinct from P13 and SIV(mac)239. The majority of the amino acid changes in the antigenically distinct viruses were clustered in V4 (amino acids 413-418) and these changes created new potential N-linked glycosylation sites. This study demonstrates that a small number of specific amino acid changes (amino acids 412 to 418 in the env gene) in the V4 region of the SIV envelope glycoprotein can alter antibody recognition and neutralization and that these phenotypic changes may be associated with altered glycosylation of the envelope.
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