The nonhuman primate SHIV model has played a crucial role in the development of anti-HIV treatment strategies. Studies with a number of pathogenic SHIV viruses have been performed at our Primate Center. This model has shown distinct disease patterns, which directly parallel the spectrum of disease seen in HIV-infected patients. SIV- and SHIV-infected monkeys have similar clinical and surrogate markers of infection such as antiviral antibodies, hematopoietic abnormalities, and virus load in the peripheral circulation and lymphoid tissues as HIV-infected patients. The importance of the SIV- and SHIV-infected monkey model lies in the fact that, unlike the human population, the timing of infection can be controlled and findings can be quantified and directly correlated with disease under controlled conditions. SHIV chimeras were created by inserting the HIV-1 env, rev, tat, and vpu genes on a background of SIVmac and were shown to readily infect macaques. By animal passage starting with an initially avirulent SHIV, a number of laboratories developed highly virulent strains. The SHIV/macaque model offers all the advantages of the SIVmac/macaque model. Infected macaques develop CD4[+] T-cell loss usually in a few weeks and develop AIDS at intervals ranging from a few weeks to two years. Histological changes in the lymphoid and other tissues closely resemble those seen in human AIDS. Infected macaques also develop organ-specific disease, including encephalitis. Thus, the SHIV/macaque model is a superb model to study AIDS gene therapy strategies. The M. nemestrina model is also an outstanding model for the testing of genetically modified stem cells. We have published extensively on the use of M. nemestrina monkeys to improve gene transfer to hematopoietic stem cells. The core leader, Dr. Kiem, has extensive experience with nonhuman primate studies. Dr. Kiem has more than 15 years experience with nonhuman primate transplantation and cellular modification studies. Thus, the specific aim of this core will be as follows: 1) Assist investigator with the CD34 isolation and ex vivo manipulation. 2) Critical care following transplantation until hematopoietic recovery 3) In vivo selection of gene modified cells in monkeys 4) Peripheral blood harvest by apheresis
The proposed research will use a highly clinically relevant monkey model to test the efficacy and safety of gene therapy strategies for the treatment of AIDS. If successful, the proposed studies will lead to novel stem cell gene therapy approaches to protect individuals from AIDS.
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