Next-generation bNAbs for HIV-1 cure strategies

Despite the ability to suppress viral replication using anti-retroviral therapy (ART), HIV-1 remains a global public health problem. Curative strategies for HIV-1 have to target and eradicate latently infected cells across the body, i.e. the viral reservoir. Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to neutralize virions and bind to infected cells to initiate elimination of these cells. To improve the efficacy of bNAbs in terms of viral suppression and viral reservoir eradication, next generation antibodies (Abs) are being developed that address the current limitations of Ab treatment efficacy; (1) low antigen (Env) density on (reactivated) HIV-1 infected cells, (2) high viral genetic diversity, (3) exhaustion of immune cells and (4) short half-life of Abs. In this review we summarize and discuss preclinical and clinical studies in which anti-HIV-1 Abs demonstrated potent viral control, and describe the development of engineered Abs that could address the limitations described above. Next generation Abs with optimized effector function, avidity, effector cell recruitment and immune cell activation have the potential to contribute to an HIV-1 cure or durable control. •There is a need for HIV-1 cure strategies that aim for reservoir reduction and durable control.•Anti-HIV-1 bNAbs delay viral rebound, induce cellular immunity and have the capacity to reduce the viral reservoir in PWH.•The efficacy of bNAb treatment is hampered by Env density, immune cell exhaustion, viral diversity, and antibody half-life.•Next-generation engineered bNAbs that overcome these limitations are of great interest for future clinical trials.