Natural killer cell engineering to target the HIV reservoir

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ABSTRACT HIV continues to be a global health concern that has claimed the lives of millions. Although anti-retroviral therapy (ART) slows disease progression, ART is not curative due to certain reservoirs of replication-competent virus that persist during therapy. Therefore, if ART is stopped, then virus can emerge from these reservoirs and rapidly spread, causing renewed progression towards AIDS. In addition, life-long use of ART is associated with issues related to cost, medical compliance, and adverse drug events. One strategy for clearing the reservoir of latently infected cells is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, and then concurrently cleared or “killed”. Latency reversal agents (LRA) can “kick” or induce HIV expression from latent cells, but thus far only a subset of activated latent cells die. Natural killer (NK) cells hold great promise as killing agents for HIV-infected cells as they re-emerge from latency due to their innate anti-viral recognition and cytotoxic function. The goal of this research project is to develop new methods to enhance the intrinsic killing activity of NK cells and to develop NK cell-based kick and kill strategies to reduce the need for life-long ART by decreasing or eliminating latent viral reservoirs. We intend to approach this proposal by using cutting-edge technology to engineer the enhanced survival and anti-viral function of NK cells, sophisticated humanized mouse models of HIV latency, and innovative tools to measure and study the effect of our treatments on the HIV reservoir. We will test our overall hypothesis that a kick and kill approach will decrease or eliminate the latent reservoir in the following aims: 1) engineer NK cells to enhance their elimination of HIV-infected cells using an innovative non-viral mRNA transfection technology, and 2) investigate the effect of novel latency reversal agents (LRAs) in combination with modified NK cells on HIV reservoirs in a humanized mouse model of HIV latency. This proposal utilizes Dr. Jerome Zack's (lead PI, UCLA) extensive background in HIV latency and animal modeling, Dr. Catherine Blish's (dual-PI, Stanford) expertise in NK cell immunobiology and cellular manipulation, and includes a unique collaboration with Dr. Paul Wender (Stanford), an expert in chemical synthesis, who has developed a globally unique library of latency reactivating agents (LRAs) with unprecedented latency reversal capabilities and expanded tolerability that will be tested individually and in synergistic combinations with NK cells. Together we hope to fully harness the potential of NK cellular therapies, and develop LRA and NK cell combination therapeutic approaches to provide patients with sustained virologic remissions or complete viral eradication.