Development of Broadly Neutralizing Nanobodies for Advancing AIDS Therapy

Abstract Human Immunodeficiency Virus (HIV) remains a persistent global health crisis, affecting approximately 39 million individuals worldwide, despite considerable advancements in prevention and treatment. While strides have been made with antiretroviral therapies (ART) and other interventions, managing HIV continues to pose significant challenges. Broadly neutralizing antibodies (bnAbs) have emerged as promising tools against HIV-1. However, their widespread use faces hurdles such as resistance development and complex administration. Consequently, exploring alternative strategies, notably nanobodies, gains prominence in HIV research. Nanobodies, recognized for their compact structure, effective tissue penetration, and unique epitope recognition, offer a novel avenue for combatting HIV. This study concentrates on harnessing diverse nanobody development strategies to identify and engineer these smaller antibodies, with a specific focus on targeting multiple sites on the HIV virus Env protein. The primary goal is to bolster treatment effectiveness while simplifying therapeutic protocols. Empirical evidence suggests that engineered antibodies, simultaneously targeting diverse sites on the HIV Env, may outperform traditional bnAbs in efficacy against a range of HIV strains. Our proposal outlines three primary objectives: first, identifying versatile nanobodies capable of recognizing various regions of the HIV Env through advanced phage-display screening; second, conducting comprehensive characterization, including neutralization studies, bioinformatic, and structural analyses, to deepen our understanding of these nanobodies' mechanisms; and finally, enhancing their efficacy by leveraging structural insights for rational design to broaden their targeting capabilities. This thorough exploration into nanobody-based therapies holds significant potential to revolutionize HIV treatment strategies. By potentially overcoming existing limitations and offering innovative pathways in HIV management, these advancements could substantially impact the ongoing battle against this persistent viral challenge.