Resist to persist: resistance of the HIV reservoir to immune-mediated clearance

Purpose of review This review examines recent research on the mechanisms underlying resistance to cytotoxic T lymphocyte (CTL)-mediated killing, commonly referred to as ‘CTL-resistance’, which contributes in the persistence of the HIV-1 reservoir and represents a major barrier to achieving an HIV-1 cure. Recent findings Recent discoveries have revealed that the viral reservoir in people with HIV (PWH) in long-term antiretroviral (ART) treatment is enriched within cells exhibiting a pro-survival phenotype, reduced antigen presentation capacity, or intrinsic mechanisms that may directly counteract cytotoxic responses, thereby facilitating immune-killing evasion. Among many others, overexpression of the antiapoptotic protein BCL-2, the pro-survival factor BIRC-5/SURVIVIN and its upstream regulator OX40, the histone methyltransferase EZH-2, or a quiescent metabolic profile with reduced reactive oxygen species production have been described as the most notable mechanisms of CTL-resistance. Summary While several advances in HIV therapeutic vaccines have demonstrated its ability to induce strong polyfunctional CTL responses associated with improved viral control, vaccine-induced responses fail to reduce reservoir levels- which might be partially due to a CTL-resistant HIV reservoir able to evade immune-mediated clearance. Strategies aimed at reversing this CTL-resistance or sensitize the HIV-1 reservoir might improve the efficacy of future immunotherapies aimed at achieving a durable ART-free control.