The emerging role of small CD4 mimetic compounds in HIV-1 immunotherapy

PURPOSE OF REVIEW: Although current antiretroviral therapy effectively suppresses HIV-1 replication, it does not eliminate infected cells. The virus persists in a latent form within long-lived reservoir cells, leading to viral rebound after treatment interruption. Developing novel therapeutic strategies capable of targeting and eliminating these persistent reservoirs remains a major obstacle to achieving a cure. This review explores the emerging role of CD4 mimetic compounds (CD4mc) in enhancing nonneutralizing antibody (nnAb)-based HIV-1 immunotherapies. RECENT FINDINGS: We review recent advances in the development of distinct families of CD4mc, focusing on their ability to prevent viral entry, sensitize HIV-1 virions and infected cells to nnAb-mediated immune responses, and block the immunomodulatory activities of soluble gp120. We also discuss the design of nnAb-CD4mc cocktails and fusion molecules, and the evidences supporting their in vitro and in vivo efficacy. SUMMARY: CD4mc exhibit multifunctional activities that enhance nnAb-based HIV-1 immunotherapies. They represent a promising component of future strategies aimed at eliminating the HIV-1 reservoir.