Characterization of a Neutralization-Escape Variant of SHIVKU-1, a Virus That Causes Acquired Immune Deficiency Syndrome in Pig-Tailed Macaques

Abstract

A chimeric simian-human immunodeficiency virus (SHIV-4) containing thetat, rev, vpu,andenvgenes 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-1binto 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 theenvgene and compared these sequences with those of theenvgene of SHIVKU-1and parental SHIV-4. With reference to SHIV-4, SHIVKU-1bhad 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-1and SHIVKU-1bprobably evolved from a common ancestor but that SHIVKU-1bdid not evolve from SHIVKU-1. A chimeric virus, SHIVKU-1bMC17, constructed with the consensusenvfrom the SHIVKU-1bon 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-1in pig-tailed macaque resulted in the selection of a neutralization-resistant virus that was responsible for the second wave of viremia.