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 SIVmac239 was used to develop an animal model in which a primate lentivirus expressing the HIV-1 envelope glycoprotein caused acquired immune deficiency syndrome (AIDS) in macaques. An SHIV-infected pig-tailed macaque that died 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 death. Virus (SHIVKU-1) isolated during the first wave was neutralized by antibodies appearing at the end of the first viremic phase, but the virus (SHIVKU-1b) isolated during the second viremic phase was not neutralized by these antibodies. Inoculation of SHIVKU-1b into 4 pig-tailed macaques resulted in severe CD4(+) T cell loss by 2 weeks postinoculation, and all 4 macaques died from AIDS at 23-34 weeks postinoculation. Because this virus had a neutralization-resistant phenotype, we sequenced the env gene and compared these 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 substitutions 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 SHIVKU-1. Our data suggested that SHIVKU-1 and SHIVKU-1b probably evolved from a common ancestor but that SHIVKU-1b did not evolve from SHIVKU-1. A chimeric virus, SHIVKU-1bMC17, constructed with the consensus env from the SHIVKU-1b on a background of SHIV-4, confirmed that amino acid substitutions in Env were responsible for the neutralization-resistant phenotype. These results are consistent with the hypothesis that neutralizing antibodies induced by SHIVKU-1 in pig-tailed macaque resulted in the selection of a neutralization-resistant virus that was responsible for the second wave of viremia. Copyright 1999 Academic Press.