Survey Article on the Shock and Kill Method

Human immunodeficiency virus is a virus that weakens your body's immune system by destroying CD4 (T-cell) lymphocytes. HIVs have an RNA genome and depend on the enzyme reverse transcriptase to transform their RNA into DNA within the host cells. This DNA is integrated into the host’s genetic material by another enzyme called integrase, allowing the virus to take control of the cell's machinery to generate more viral particles. A vital approach to eliminate HIV is the shock and kill method, which seeks to reactivate the latent reservoir using latency-reversing agents (LRAs) and also allows for the removal of these cells through immune-mediated clearance or viral cytopathic effects. The goal of the shock and kill method is to completely get rid of the virus from the body, unlike current HIV treatments that only suppress it. In a survey of peer-reviewed human and animal studies, we find that LRAs reliably induce HIV transcription in vivo but rarely contract intact proviral reservoirs; combinations with therapeutic vaccines, broadly neutralizing antibodies, or checkpoint blockade produce mixed reservoir effects and modest rebound delays, while nonhuman primate regimens pairing TLR7 agonists with vaccines or bNAbs achieve partial post-treatment control. Early-infection interventions at ART initiation outperform late shock-and-kill in chronic infection. Adverse events are generally mild, yet global T-cell activation and incomplete clearance remain key limitations. We propose DNA origami nanostructures as a precise, stimulus-responsive delivery platform to co-localize LRAs and killing effectors at reservoir sites—a strategy not yet tested in HIV cure trials. Overall, targeted, multipronged delivery will be essential to translate shock-and-kill into durable remission or cure.