DESCRIPTION (provided by applicant): Although modern therapies have dramatically improved the outlooks for people living with HIV/AIDS (PLWHA) they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to expensive antiretroviral medication. It has also become clear that these treatments do not fully restore health, nor do they address the negative social issues associated with being HIV positive, including stigma and issues related to criminalization. The development of a safe and effective HIV cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV infection is the establishment of reservoirs of hidden or `latent' virus which evade the immune system and can re-seed infection if an individual stops antiretroviral therapy. In this project, we are pursuing a novel approach to engineer the immune system target and eliminate this latent HIV reservoir. The body has several types of immune responses with the potential to contribute to the eradication of HIV reservoirs including i) the killer T-cell response (or CD8 T-cell response) involving a type of cell that can recognize and kill virus infected cells ii) the antibod response (from a different type of cell, B cells) which can both bind to and inactivate virus in th blood and can bind to and label virus-infected cells iii) the natural killer response, involving another type of cell that specifically kills infected cells that have been labeled with antibody. W will create synergy between these systems by endowing HIV-specific killer T-cells with the ability to produce HIV-specific antibodies. This production of antibodies will be tightly controlle to only occur when these killer T- cells either encounter an HIV-infected cell, or when they are stimulated by a drug that also pushes HIV out of hiding, a `latency reversing agent or LRA'. The ultimate aim of this work is to develop a therapeutic intervention where PLWHA are treated with both these engineered cells and LRAs. The LRAs will both expose HIV reservoirs and trigger this tripartite immune attack on these unmasked target cells, leading to viral clearance and hopefully to cures.

PUBLIC HEALTH RELEVANCE: Although HIV infection can be controlled by daily lifelong adherence to expensive antiretroviral therapies it cannot presently be cured. Eradicating virus from a person will likely require the co-ordination of drugs that expose hidden viral reservoirs (latency reversing drugs) with the effective harnessing of multiple arms of the immune system. We are developing a potentially curative therapeutic platform of engineered killer T-cells that, upon triggering by latency reversing drugs, will direct three arms of the immune system against the viral reservoirs that the drugs will simultaneously expose.