A SHIV MODEL FOR EVALUATING HIV IMMUNOTHERAPIES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Because most studies of AIDS pathogenesis in nonhuman primates have been performed in Indian-origin rhesus macaques (M. mulatta), little is known about lentiviral pathogenicity and control of virus replication following infection of alternative macaque species. Here, we report the consequences of SHIV-89.6P and SIVmac251 infection in cynomolgus (M. fascicularis) and rhesus macaques of Chinese-origin. Compared to the pathogenicity of the same viruses in Indian rhesus, both cynomolgus and Chinese rhesus showed lower levels of plasma virus. By 9-10 months after infection, both viruses became undetectable in plasma more frequently in cynomolgus than in either Chinese or Indian rhesus. Furthermore, CD4+T cell numbers declined less in cynomolgus and Chinese rhesus than in Indian rhesus after SHIV-89.6P infection. Survival after SHIV-89.6P infection was longer in both cynomolgus and Chinese rhesus cohorts than in Indian rhesus. This attenuated pathogenicity was associated with ELISPOT responses to Gag and Env that were generated earlier and of higher frequency in cynomolgus than in Indian rhesus macaques. Cynomolgus also developed higher titer neutralizing antibodies at 10 and 20 weeks post-inoculation against SHIV-89.6 than Indian rhesus. These studies demonstrate that the pathogenicity of nonhuman primate lentiviruses vary markedly in different macaque species or subspecies and implicate the cellular immune responses in the control of pathogenicity in cynomolgus macaques. While cynomolgus and Chinese rhesus macaques provide alternative animal models of lentiviral infection, the lower levels of viremia in cynomolgus macaques limit the usefulness of infection of this species for vaccine trials that utilize viral load as an experimental endpoint.