Characterization of a neutralization-escape variant of SHIVKU-1, a virus that causes acquired immune deficiency syndrome in pig-tailed macaques

A chimeric simian-human immunodeficiency virus (SHIV-4) containing the tat, rev, vpu, and env genes of HIV type 1 (HIV-1) in a genetic background of S IVmac 239 was used to develop an animal model in which a primate lentivirus expressing the HIV-1 envelope glycoprotein caused acquired immune deficien cy syndrome (AIDS) in macaques. An SHIV-infected pig-tailed macaque that di ed from AIDS at 24 weeks postinoculation experienced two waves of viremia: one extending from weeks 2-8 and the second extending from week 18 until de ath. Virus (SHIVKU-1) isolated during the first wave was neutralized by ant ibodies appearing at the end of the first viremic phase, but the virus (SHI VKU-1b) isolated during the second viremic phase was not neutralized by the se antibodies. Inoculation of SHIVKU-1b into 4 pig-tailed macaques resulted in severe CD4(+) T cell loss by 2 weeks postinoculation, and all 4 macaque s died from AIDS at 23-34 weeks postinoculation. Because this virus had a n eutralization-resistant phenotype, we sequenced the env gene and compared t hese sequences with those of the env gene of SHIVKU-1 and parental SHIV-4. With reference to SHIV-4, SHIVKU-1b had 18 and 6 consensus amino acid subst itutions in the gp120 and gp41 regions of Env, respectively. These compared with 10 and 3 amino acid substitutions in the gp120 and gp41 regions of SH IVKU-1. Our data suggested that SHIVKU-1 and SHIVKU-1b probably evolved fro m a common ancestor but that SHIVKU-1B did not evolve from SHIVKU-1. A chim eric virus, SHIVKU-1bMC17 constructed with the consensus env from the SHIVK U-1b on a background of SHIV-4 confirmed that amino acid substitutions in E nv were responsible for the neutralization-resistant phenotype. These resul ts are consistent with the hypothesis that neutralizing antibodies induced by SHIVKU-1 in pig-tailed macaque resulted in the selection of a neutraliza tion-resistant virus that was responsible for the second wave of viremia. ( C) 1999 Academic Press.