Researchers from the Perelman School of Medicine and the Penn Center for AIDS Research (CFAR) have been awarded $7.5 million over five years from the National Institutes of Health to initiate a multi-project HIV study investigating a new gene therapy approach to render immune cells of HIV positive patients resistant to the virus.

The project, entitled “Engineering T cells to Provide Durable Control of HIV-1 Replication,” includes principal investigator James L. Riley, PhD, associate professor of Microbiology, Pablo Tebas, MD, professor of Medicine and director of the AIDS Clinical Trials Unit at the Penn CFAR,James Hoxie, MD, professor of Medicine at Penn and director of the Penn CFAR, Michael C. Holmes, PhD, VP Research at Sangamo BioSciences Inc.,  E. John Wherry, PhD, professor of Microbiology and director of the Institute for Immunology, and  Frederick D. Bushman, PhD, professor of Microbiology. 

The Penn-led team, in collaboration with Sangamo, will investigate the ability of a synthetic molecule consisting of a viral entry inhibitor called C34 fused to CXCR4, an HIV co-receptor used by the virus to enter and infect T cells.  Building upon the success of past studies that utilized a zinc finger nuclease (ZFN) technology to disrupt the other major viral entry factor, CCR5, the new Penn project—in both preclinical and clinical studies—aims to safely build an army of modified, HIV-1 resistant T cells in HIV infected patients using a lentiviral technology to express the C34-CXCR4 molecule. This approach, researchers believe, will make more CD4 T cells resistant to the virus and thus may re-invigorate the immune response to control HIV-1 replication in the absence of antiretroviral drug therapy (ADT).

The grant is funded under NIH’s U19 Research Program, which funds collaborative projects involving multiple institutions, including an industry collaborator. The purpose of this funding opportunity, supported by the National Institute of Allergy and Infectious Disease, National Heart, Lung, and Blood Institute, and the National Institute of Mental Health, is to encourage investigators to work together on innovative approaches to eliminate HIV and leverage the expertise and resources of the participating institutes.

For the preclinical work on the Penn project, researchers will learn more about how the mechanism by C34-CXCR4 provides such robust protection of CD4 T cells and apply chimeric antigen receptor (CAR) technology to re-direct the HIV-1 immune response, among other laboratory efforts. As part of the phase I study, researchers will manufacture the engineered T cells (taken from a patients’ own immune system) and then infuse them back into HIV infected patients taken off ADT to determine their resistance and survival abilities and anti-viral effects.

The work is an important extension of the HIV gene therapy work conducted by researchers at the Penn CFAR and the Perelman School of Medicine over the last decade.

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