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

Abstract

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 SIV(mac)239 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 (SHIV(KU-1)) isolated during the first wave was neutralized by antibodies appearing at the end of the first viremic phase, but the virus (SHIV(KU-1b)) isolated during the second viremic phase was not neutralized by these antibodies. Inoculation of SHIV(KU-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 SHIV(KU-1) and parental SHIV-4. With reference to SHIV-4, SHIV(KU-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 SHIV(KU-1). Our data suggested that SHIV(KU-1) and SHIV(KU-1b) probably evolved from a common ancestor but that SHIV(KU-1b) did not evolve from SHIV(KU-1). A chimetic virus, SHIV(KU-1bMC17), constructed with the consensus env from the SHIV(KU-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 SHIV(KU-1) in pig-tailed macaque resulted in the selection of a neutralization-resistant virus that was responsible for the second wave of viremia.