Proteasome Inhibition Reactivates Latent HIV‐1 and Boosts NK Cell Killing via HLA‐E Downregulation

The shock-and-kill strategy aims to eliminate the human immunodeficiency virus type 1 (HIV-1) reservoir by reactivating latent virus with latency-reversing agents, thereby making infected cells visible for immune-mediated clearance. Despite promising in vitro and ex vivo results, clinical trials have shown limited success, likely due to the heterogeneity and inefficient elimination of reactivated cells by immune effectors such as natural killer (NK) cells. One barrier to NK cell function is the inhibitory NKG2A-HLA-E interaction, which dampens antiviral responses. Proteasome inhibition has been shown in cancer models to downregulate HLA-E and enhance NK-cell cytotoxicity, but its effect on HIV-1 latency remains unexplored. In this study, we demonstrate that proteasome inhibition not only reverses latency in HIV-1-infected cell lines and primary CD4+ T cells but also reduces HLA-E expression. Additionally, proteasome inhibition lowered NKGA levels on NK cells, further enhancing their cytotoxic capacity. Together, these findings suggest that proteasome inhibition could simultaneously boost both phases of the shock-and-kill strategy, by reactivating latent HIV-1 and by improving NK cell-mediated clearance through disruption of the NKG2A-HLA-E axis. This dual effect may significantly strengthen the "kill" phase of the shock-and-kill approach and could represent a promising path toward achieving a functional HIV-1 cure.