The favored initial approach by many to depleting HIV reservoirs and achieving an HIV cure was the “shock and kill” strategy, consisting of “shocking” proviruses out of latency and killing the cells with newly expressed viral antigens, either by direct viral-mediated cytotoxicity or immune-mediated clearance. However, in vitro models showed that proviral latency reversal alone did not result in death of infected cells (Shan, et al. Immunity 2012). Ex vivo experiments revealed that only a small fraction of proviruses (~1.5%) can be reactivated to produce virions with maximum CD4+T-cell activation, and that <<1% are reactivated with current, small molecule latency reversing agents (Cillo, et al. PNAS 2014). In addition, maximum CD4+T-cell activation can cause the expansion of clones carrying intact proviruses capable of sustained production of infectious virus (Bui, et al PLoS Pathogens 2017). With regard to immune-mediated killing of infected cells, increasing antibody-dependent effector functions including ADCC, ADCP, and ADCF is a popular approach, but a recent trial (ACTG A5342) of two doses (40 mg/kg) of the bnMAb VRC01 revealed that is had no effect on persistent viremia and did not decrease the number infected cells in blood or the subset expressing viral RNA. Although many more approaches to “shock and kill” are in development and being tested alone and in combination, these initial data summarized above suggest that the goal of reservoir depletion may be more difficult to achieve than anticipated because of barriers to latency reversal and resistance of infected cells to immune-mediated clearance.