Recent rollbacks of foreign aid programs has destabilised antiretroviral therapy (ART) supply chains and threaten progress made to control HIV/AIDS. No curative alternative to ART currently exists. The conceptually most advanced cure approach is the ‘shock-and-kill’ strategy, proposing the pharmacological reactivation of immunologically evasive, latently HIV-1-infected cells, inducing renewed viral component synthesis, to promote immune-mediated detection and clearance of infected cells. However, this has so far been clinically unsuccessful. To investigate this, we generated a novel in vitro model of HIV-1 latency consisting of Jurkat T-cell-derived clonal cell lines, each harbouring a single latent provirus with a GFP-reporter fused to the viral glycoprotein, Env. This model allows tracking of latency reversal, as well relative cell surface presentation of the Env-GFP reporter – a crucial determinant for antibody-dependent recognition and immune clearance. Crucially, we identified the HIV-1 accessory protein, Nef, which is co-induced by latency reversal, as a clear hurdle to immune-mediated killing. CRISPR/Cas9-mediated knockout of the nef gene significantly improved the susceptibility of reactivated cells to intrinsic apoptosis, extrinsic apoptosis and antibody-dependent cellular cytotoxicity, while boosting cell-surface presentation of Env. Currently, we are investigating small-molecule PROteolysis-TArgeting Chimera (PROTAC)-mediated degradation of the Nef protein as a therapeutic potentiator for ‘shock-and-kill’. In parallel, we are performing in silico analysis of novel, rationally designed small molecule Nef degraders with improved drug-likeness, in comparison to the existing Nef PROTAC FC-14369. Combining latency reversal with pharmacologically induced Nef degradation to enhance immune clearance presents a novel, combinatorial therapy approach toward a scalable HIV-1 cure.