Mechanisms of CTL Resistance in HIV Reservoirs

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. It would therefore be of tremendous value to develop novel therapies that can either cure HIV infection or drive it into remission (a state where levels of virus remain low or undetectable even when one stops taking ARV medication). One approach to achieving either a cure or remission is to reactivate latent (hidden) ‘reservoirs’ of virus and harness the immune system to reduce or eliminate these reservoirs. These ‘kick & kill’ approaches often focus on cytotoxic T-cells (CTL), which are an arm of the immune system specialized in eliminating virus-infected cells. While the ‘kick & kill’ strategy has shown promise in in vitro models of latency, it has not yet been effective in clinical trials. In recent work, we have uncovered an additional barrier to eliminating viral reservoirs by showing that HIV-infected cells are intrinsically resistant to CTL - even when they are forced to show virus to the immune system by latency reversing agents (LRAs). Although this idea of intrinsic resistance to CTL has not been widely considered in the context of HIV, it is well known as a factor that limits therapeutic efficacy in cancer. In this grant application we propose to leverage cutting edge technologies to identify novel mechanisms by which target cells resist elimination by CTL. These approaches are expected to yield a large number of ‘hits’, for which we will perform high-resolution mechanistic characterizations. We will then study samples from people living with HIV to determine which of these mechanisms of resistance play roles in HIV persistence in vivo. Finally, we will directly test whether therapies targeting this resistance can allow CTL to kill these ex vivo reservoir-harboring cells. We expect that the outcome of our study will be the identification of novel targets for the development of therapies aimed at curing HIV infection or enabling remission. More broadly, we anticipate that the mechanisms identified here will provide fundamental insights into the biology of CTL with implications for cancer & other conditions.