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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096111-03
Application #
8497610
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$641,192
Indirect Cost
$86,451
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Cannon, Paula M; Kohn, Donald B; Kiem, Hans-Peter (2014) HIV eradication--from Berlin to Boston. Nat Biotechnol 32:315-6
Boissel, Sandrine; Jarjour, Jordan; Astrakhan, Alexander et al. (2014) megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering. Nucleic Acids Res 42:2591-601
Younan, Patrick; Kowalski, John; Kiem, Hans-Peter (2014) Genetically modified hematopoietic stem cell transplantation for HIV-1-infected patients: can we achieve a cure? Mol Ther 22:257-64
Baxter, Sarah K; Scharenberg, Andrew M; Lambert, Abigail R (2014) Engineering and flow-cytometric analysis of chimeric LAGLIDADG homing endonucleases from homologous I-OnuI-family enzymes. Methods Mol Biol 1123:191-221
Weber, Nicholas D; Aubert, Martine; Dang, Chung H et al. (2014) DNA cleavage enzymes for treatment of persistent viral infections: recent advances and the pathway forward. Virology 454-455:353-61
Matrajt, Laura; Younan, Patrick M; Kiem, Hans-Peter et al. (2014) The majority of CD4+ T-cell depletion during acute simian-human immunodeficiency virus SHIV89.6P infection occurs in uninfected cells. J Virol 88:3202-12
Kuhar, Ryan; Gwiazda, Kamila S; Humbert, Olivier et al. (2014) Novel fluorescent genome editing reporters for monitoring DNA repair pathway utilization at endonuclease-induced breaks. Nucleic Acids Res 42:e4
Hall Sedlak, Ruth; Jerome, Keith R (2014) The potential advantages of digital PCR for clinical virology diagnostics. Expert Rev Mol Diagn 14:501-7
Sedlak, Ruth Hall; Jerome, Keith R (2013) Viral diagnostics in the era of digital polymerase chain reaction. Diagn Microbiol Infect Dis 75:1-4
Peterson, C W; Younan, P; Jerome, K R et al. (2013) Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART. Gene Ther 20:695-702

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