Which therapeutic strategy will achieve a cure for HIV-1?

•Eradication, functional, and hybrid cures for HIV-1 are under investigation.•'Kick and kill' has been the most intensively studied curative strategy to date.•HIV-1 latency reversing agents have increased cellular HIV-1 RNA in vivo.•Whether latency reversing agents are safe and can deplete the reservoir is unknown.•Boosting immunologic control of HIV-1 should be pursued as part of a hybrid cure.

Strategies to achieve a cure for HIV-1 infection can be broadly classified into three categories: eradication cure (elimination of all viral reservoirs), functional cure (immune control without reservoir eradication), or a hybrid cure (reservoir reduction with improved immune control). The many HIV-1 cure strategies being investigated include modification of host cells to resist HIV-1, engineered T cells to eliminate HIV-infected cells, broadly HIV-1 neutralizing monoclonal antibodies, and therapeutic vaccination, but the 'kick and kill' strategy to expose latent HIV-1 with latency reversing agents (LRAs) and kill the exposed cells through immune effector functions is currently the most actively pursued. It is unknown, however, whether LRAs can deplete viral reservoirs in vivo or whether current LRAs are sufficiently safe for clinical use.