Proteasome inhibition enhances latency reversal and boosts NK cell-mediated elimination of HIV-1 infected cells through HLA-E downregulation

The shock and kill strategy primarily depends on using latency reversal agents (LRAs) to reactivate the dormant viral reservoir, rendering it visible for recognition and subsequent elimination by the hosts immune system. While this approach has shown high efficacy in vitro and ex vivo, its in vivo application has yet to show significant delays in time to viral rebound. This lack of in vivo efficacy is most likely due to the insufficient elimination of reactivated reservoir cells by the hosts immune effector cells, including natural killer (NK) cells. Given the pivotal role of NK cells in antiviral immune responses, we hypothesized that they are crucial players in pursuing a functional cure against HIV-1. However, the inhibitory interaction between NKG2A and HLA-E diminishes their effectiveness. Notably, proteasome inhibition has been effective in reducing HLA-E expression on various tumor cell types, thereby enhancing NK-cell mediated killing. However, its impact on HIV-1 latency remains unexplored. We found that the proteasome inhibition could reverse the latent state of J-Lat cells while substantially reducing HLA-E expression. Additionally, a reduced expression of NKGA on primary NK cells was observed which led to an increase in NK-cell cytotoxicity. These results suggest that disrupting the NKG2A/HLA-E interaction could potentially augment the effectiveness of the shock and kill strategy by improving NK cell-mediated clearance of reactivated cells. ImportanceDespite promising in vitro results, purging the viral reservoir using LRAs has yet to demonstrate clinical benefits. A significant challenge lies in the inadequate activation of immune effector cells, such as CD8+ T cells and NK cells. Therefore, developing therapeutic strategies to address these challenges could enhance the effectiveness of the shock and kill strategy. This study highlights the need for therapeutic interventions to overcome these hurdles. Our findings show that proteasome inhibition not only triggers latency reversal but also enhances NK-cell mediated elimination of latently infected cells in vitro by downregulating HLA-E. This suggests that targeting the proteasome could be a novel therapeutic approach in the shock and kill strategy, potentially improving clinical outcomes.