Adoptive T cell immunotherapy provides an attractive alternative to the current regime of antiretroviral medication for the treatment of HIV disease because it has the potential to be highly specific, long lasting, and free of significant side effects. Key to the success of adoptive T cell therapy is survival and retained functional capabilities of the T cells once they are re-infused into the host. The ex vivo expansion phase of adoptive T cell immunotherapy provides an opportunity to genetically engineer T cells to modify their resistance to HIV infection once re-infused into the host. The central hypothesis of this application is that T cells can be engineered so that they are immune to HIV entry and integration in vivo. We will undertake two approaches to engineer T cells to become resistant to HIV entry and integration. The first will make a multi-targeted lentiviral vector that will encode a humanized version of the rhesus TRIMSa, a cell based T-20-like fusion inhibitor, and/or a small hairpin (sh) RNA that targets CCR5 mRNA. We will employ both in vitro and in vivo HIV challenge assays as well as T cell functional assays to identify the best combination of antiviral agents. The second approach attempts to replicate the innate high resistance to HIV infection observed in individuals who are homozygous for a 32 base pair deletion in their CCR5 gene. By using zinc finger nucleases (ZFNs) specific to CCR5 we will induce double strand breaks in the CCR5 coding region. These double strand breaks will invoke the highly error prone non-homogologous end joining repair mechanism to make mutations that disrupt the production of functional CCR5. It is our hypothesis that T cells engineered in this manner we will have a competitive advantage in repopulating immunocomprised HIV infected individuals and serve to fight both HIV and opportunistic infections. This hypothesis will be tested in a Phase I clinical trial described in Project 1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066290-03
Application #
7549277
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$298,810
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Riley, James L; Montaner, Luis J (2017) Cell-Mediated Immunity to Target the Persistent Human Immunodeficiency Virus Reservoir. J Infect Dis 215:S160-S171
Levine, Bruce; Leskowitz, Rachel; Davis, Megan (2015) Personalized gene therapy locks out HIV, paving the way to control virus without antiretroviral drugs. Expert Opin Biol Ther 15:831-43
Richardson, Max W; Guo, Lili; Xin, Frances et al. (2014) Stabilized human TRIM5? protects human T cells from HIV-1 infection. Mol Ther 22:1084-1095
Tebas, Pablo; Stein, David; Tang, Winson W et al. (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370:901-10
Maier, Dawn A; Brennan, Andrea L; Jiang, Shuguang et al. (2013) Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther 24:245-58
Tebas, Pablo; Stein, David; Binder-Scholl, Gwendolyn et al. (2013) Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV. Blood 121:1524-33
Gijsbers, Rik; Vets, Sofie; De Rijck, Jan et al. (2011) Role of the PWWP domain of lens epithelium-derived growth factor (LEDGF)/p75 cofactor in lentiviral integration targeting. J Biol Chem 286:41812-25
Mukherjee, Rithun; Plesa, Gabriela; Sherrill-Mix, Scott et al. (2010) HIV sequence variation associated with env antisense adoptive T-cell therapy in the hNSG mouse model. Mol Ther 18:803-11
June, Carl H; Blazar, Bruce R; Riley, James L (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9:704-16
Wang, Gary P; Levine, Bruce L; Binder, Gwendolyn K et al. (2009) Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther 17:844-50

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