The use of nonhuman primate models of HIV infection has remained a central aspect of anti-HIV research since the outbreak of the AIDS epidemic. These models have been best characterized in vaccine studies, but more recently have demonstrated utility in pre-exposure prophylaxis and gene therapy-based anti-HIV approaches. In constructing an appropriate macaque model of HIV infection designed to evaluate curative therapies, it is important to carefully choose 1) the appropriate species, 2) optimal challenge virus, 3) effective cART regimen including demonstration of viral rebound following cART interruption, 4) timing between viral challenge and cART that best approximate the condition of a stably suppressed HIV+ patient, 5) optimal longitudinal and terminal analyses of candidate curative approaches. To address each of these five issues, we have developed a comprehensive experimental system for both Projects 1 and 4, and have developed the NHP Model and Transplantation Core (NHP-MTC) to provide unifying procedural and experimental support for both projects. Our model uses the pigtailed macaque, M. nemestrina (PTM), a CCR5-tropic env-SHIV (SHIV1157-ipd3N4, a.k.a. SHIV-C), and a three-drug cART regimen including the reverse transcriptase inhibitors PMPA and FTC, and the integrase inhibitor Raltegravir. Finally, in order to better model the clinical course of infection, we have constructed an extended experimental timeline, including 24-week spacing between each of the three experimental stages of virus challenge?cART initiation?autologous or allogeneic transplant. After transplant, recipients continue to be intensively monitored while on cART for at least a year, at which time we are able to assign cohorts in which the reservoir will be exhaustively interrogated through terminal analysis, as well as comparative cohorts who receive planned cART treatment interruption. The experiments that will be performed in Projects 1 and 4, and supported by this Core, benefit from the fact that, in addition to its strengths as a model of HIV infection, the PTM model is also an outstanding model for the testing of genetically modified stem cells, as well as for autologous and allogeneic transplantation. Our collaborative group has extensive experience in each of these areas: We have published widely on the use of M. nemestrina monkeys to improve gene transfer to hematopoietic stem cells (HSCs), as well as on autologous and allogeneic transplants with nonhuman primates. Dr. Kiem has extensive experience with nonhuman primate studies, with more than 20 years' experience with nonhuman primate transplantation and cellular modification studies. In addition, Dr. Kean has more than 12 years of experience in autologous and allogeneic transplantations studies in NHP. She has pioneered the use of MHC-defined primate colonies for transplantation studies and has created the only NHP model of graft-versus-host disease in existence.. Both Dr. Kiem and Dr. Kean will assist Dr. Hu, the Core leader of this NHP Model and Transplantation (MTC) in organizing and conducting the proposed core functions.
Novel HIV treatments are critically important to help the more than 30 million infected people worldwide. Here we propose novel HIV treatment approaches that are aimed at developing a long-term control or even cure without the need for lifelong anti retroviral drug treatments. To ensure safety for patients and also efficacy clinically relevant large animal models like our model proposed here are critically important for these studies
