Weaponsing NK cells to treat viral infections

Natural Killer (NK) cells are innate immune cells which play an important role in eliminating malignant and virally-infected cells but emerging evidence indicates they can also possess memory-like functions, analogous to T cells. Subsets of NK cells expand in response to certain viral infections and exhibit an enhanced ability to mediate cellular cytotoxicity upon re-exposure. We have shown populations of memory-like NK cells are dramatically expanded in people with HIV and remain so despite years of effective anti-HIV therapy, indicating that once induced, these memory-like cells are a very stable population. The fact that these memory NK cells have enhanced killing ability opens up the exciting possibility that they may be useful effector cells to eliminate virally-infected cells from the body in chronic infections such as HIV. We are developing immunotherapy-based strategies to target residual HIV-infected cells that persist in the body despite anti-HIV therapy as part of an approach to cure HIV. This involves identifying the relevant NK subset which is the most potent killer of HIV-infected cells, expanding and activating these cells ex vivo, then reinfusing them into people with HIV as part of a combination cure therapy. This project will help forward this immunotherapy approach by addressing the following questions: • Which subsets of NK cells exhibit the greatest killing activity against HIV-infected cells? • How common are these subsets in people with HIV? • What culture conditions are best for expanding and activating key NK cell subsets ex vivo? • Can we combine NK cells with anti-HIV antibodies to enhance elimination of HIV-infected cells? Discoveries made in this project may be applicable not only to HIV cure approaches but also more broadly to immunotherapies to target a range of chronic viral infections and cancer.