Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful - for those who can access and afford it - yet HIV infection persists indefinitely in a reservoir of cells, despite effective ART and despite host antiviral immune responses. An HIV cure is therefore the next aspirational goal and challenge, though approaches differ in their objectives - with 'functional cures' aiming for durable viral control in the absence of ART, and 'sterilizing cures' aiming for the more difficult to realize objective of complete viral eradication. Mechanisms of HIV persistence, including viral latency, anatomical sequestration, suboptimal immune functioning, reservoir replenishment, target cell-intrinsic immune resistance, and, potentially, target cell distraction of immune effectors, likely need to be overcome in order to achieve a cure. A small fraction of people living with HIV (PLWH) naturally control infection via immune-mediated mechanisms, however, providing both sound rationale and optimism that an immunological approach to cure is possible. Herein we review up to date knowledge and emerging evidence on: the mechanisms contributing to HIV persistence, as well as potential strategies to overcome these barriers; promising immunological approaches to achieve viral control and elimination of reservoir-harboring cells, including harnessing adaptive immune responses to HIV and engineered therapies, as well as enhancers of their functions and of complementary innate immune functioning; and combination strategies that are most likely to succeed. Ultimately, a cure must be safe, effective, durable, and, eventually, scalable in order to be widely acceptable and available.
