In a new study, researchers from the University of Pennsylvania's Perelman School of Medicine improved on a previous attempt to develop a genetic modification that could potentially be used to modulate a patient's own immune system cells. A new strategy to fight HIV. This method shows benefits in mice and human cells cultured in vitro. The results of the study were published in the journal PLoS Pathogens on October 12, 2017, entitled "Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor".
White blood cells, called T cells, play an important role in the immune response of the immune system to HIV, especially if the patient stops taking antiretroviral drugs (ART) that are normally under control. However, HIV takes several methods it can use to evade T cell attacks. Therefore, some scientists have proposed genetically modifying the patient's own T cells to fight HIV more effectively.
In the past, many attempts have been made to genetically engineer T cells to fight HIV, including a method that has undergone clinical testing. However, to date, no method has been successful enough to achieve a wide range of applications. Today, a new attempt by Rachel Leibman, a Ph.D. student at the University of Pennsylvania's Perelman School of Medicine, and colleagues have hopes for success.
This new technology is based on this earlier method of clinical trials. This earlier approach relies on the chimeric antigen receptor (CAR), a synthetic protein that, when introduced into T cells, allows them to be more effective against specific enemies. At the time of treatment, T cells extracted from the blood of a patient are genetically engineered in the laboratory to express HIV-specific CARs, which are then perfused back into the patient to resist the virus. (Other CAR-based technologies have succeeded in enhancing the attack that T cells have on some cancer cells.)
Using recent advances in CAR technology, Leibman and her colleagues have improved this previously clinically tested CAR protein (ie, the initial CAR). This protein consists of several different fragments, for which they systematically adjust the proteins one by one to optimize their performance. They found that T cells expressing this novel CAR prevented the virus from spreading between human cells more than 50-fold more efficiently in the laboratory than T cells expressing the original CAR.
The researchers also tested this new type of CAR in mice infected with HIV. They found that mouse T cells genetically engineered to express this novel CAR were able to protect other T cells in these mice from HIV challenge and rejection. In mice receiving antiretroviral therapy, these genetically engineered T cells delayed the rebound of the virus after this treatment was stopped.
These findings may pave the way for clinical testing using this new method of enhancing CAR to genetically engineer T cells. If successful, this approach could potentially put HIV under control without antiretroviral therapy.
The researchers explained, "Our data show for the first time that genetically engineered T cells can significantly control viral rebound without ART treatment. Our next step is to advance this concept into clinical trials."
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