PERSISTENT INFECTION OF MACAQUES WITH SIMIAN-HUMAN IMMUNODEFICIENCY VIRUSES

Chimeric simian-human immunodeficiency viruses (SHIV) containing the h uman immunodeficiency virus type 1 (HIV-1) tat, rev, env, and, in some cases, vpu genes were inoculated into eight cynomolgus monkeys. Virus es could be consistently recovered from the CD8 depleted peripheral bl ood lymphocytes of all eight animals for at least 2 months, After this time, virus isolation varied among the animals, with viruses continui ng to be isolated from some animals beyond 600 days after inoculation, The level of viral RNA in plasma during acute infection and the frequ ency of virus isolation after the initial 2-month period were higher f or the Vpu-positive viruses, All of the animals remained clinically he althy, and the absolute numbers of CD4-positive lymphocytes were stabl e, Antibodies capable of neutralizing HIV-1 were generated at high tit ers in animals exhibiting the greatest consistency of virus isolation, Strain-specific HIV-1-neutralizing antibodies were initially elicited , and then more broadly neutralizing antibodies were elicited. env seq uences from two viruses isolated more than a year after infection were analyzed. In the Vpu-negative SHIV, for which virus loads were lower, a small amount of env variation, which did not correspond to that fou nd in natural HIV-1 variants, was observed, By contrast, in the Vpu-po sitive virus, which was consistently isolated from the host animal, ex tensive variation of the envelope glycoproteins in the defined variabl e gp120 regions was observed, Escape from neutralization by CD4 bindin g site monoclonal antibodies was observed for the viruses with the lat ter envelope glycoproteins, and the mechanism of escape appears to inv olve decreased binding of the antibody to the monomeric gp120 glycopro teins. The consistency with which SHIV infection of cynomolgus monkeys is initiated and the similarities in the neutralizing antibody respon se to SHIV and HIV-1 support the utility of this model system for the study of HIV-1 prophylaxis.