Beyond monotherapy: Combination therapies for HIV-1 cure through joint application of neutralizing antibodies, genome editing, and reservoir management.

Despite its potency in suppressing HIV-1 replication, antiretroviral therapy (ART) cannot eliminate latent viral reservoirs and is associated with several limitations, such as the need for lifelong treatment and the inherent risk of drug resistance. The quest for an HIV-1 cure has progressed from monotherapeutic approaches to the combinations of multimodal strategies, including neutralizing antibodies, precision genome editing, and management of latent reservoirs. Antibody-based interventions primarily involve inducing broadly neutralizing antibodies (bNAbs) through native-like envelope (Env) trimer vaccines, with their efficacy further enhanced by mRNA-lipid nanoparticle delivery systems. Precision genome editing can be achieved by using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) along with long-acting slow-effective release antiretroviral therapy. Reservoir-targeted therapies are typically implemented by reactivating latent viruses using the "shock and kill" strategy. Engineered cellular therapies include chimeric antigen receptor T (CAR-T) cells or bispecific antibodies (bsAbs) for subsequent immune clearance, immune system reconstitution via stem cell transplantation, and reversal of T-cell exhaustion using immune checkpoint inhibitors. Despite these advances, challenges remain, including suboptimal immunogenicity of Env vaccines, off-target effects and inefficient delivery of gene editing tools, incomplete reactivation of latent viruses, and limitations of preclinical models. Future research should focus on optimizing synergistic effects by improving Env trimer design, enhancing the targeting specificity of CRISPR systems, and developing preclinical models that more accurately reflect human immunity, thereby facilitating the transition from lifelong ART to a functional cure. This review summarizes recent progress in multimodal synergistic strategies and proposes a framework for an HIV-1 cure that may also offer insights into the treatment of other chronic viral infections.