Public Release: 

Penn Medicine researchers receive $7.5 million to expand HIV gene therapy work

Penn-led team will engineer T cells to be resistant to HIV-1 infection

University of Pennsylvania School of Medicine

PHILADELPHIA--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.

Most recently, reporting in the (New England Journal of Medicine in 2014, Penn researchers successfully genetically engineered the immune cells of 12 HIV positive patients to resist infection, and decreased the viral loads of some patients taken off ADT entirely--including one patient whose levels became undetectable. The group used the ZFN technology developed by Sangamo to modify the T cells in the patients--a "molecular scissors," of sorts, to mimic the CCR5-delta-32 mutation. That rare mutation is of interest because it provides a natural resistance to the virus, but in only 1 percent of the general population. By inducing the mutations, the scientists reduced the expression of CCR5 surface proteins. Without those, HIV cannot enter, rendering the patients' cells resistant to infection. In April 2015, the researchers received the National Clinical Research Achievement Award for the paper.

"In this next trial, we hypothesize that individuals who receive engineered T cells expressing the C34-CXCR4 fusion gene will experience a significant loss in viral load for a longer period of time because we are able to protect CD4 T cells from different classes of HIV-1," Riley said. "This is an important component of the HIV gene therapy work here at Penn, as it will tell us how these approaches stack up against each other. We are ultimately trying to find effective, lasting ways to eliminate the need for lifelong ADT for HIV infected patients, and we believe these projects will help find the answers to some of the hard questions surrounding that goal."

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