Targeting the HIV-1 reservoir at cART initiation with CD4-mimetic interventions

Summary Combination antiretroviral therapy (cART) fails to eliminate HIV-1 persisting in reservoirs or prevent long-term complications in people living with HIV (PLWH); therapy interruption leads to rapid viral rebound. Therefore, new approaches aimed at eradicating HIV-1 or enabling durable virus control without cART are needed. This is an R01 application in response to the NOFO PAR-23-297: “Opportunities for HIV Cure Strategies at the Time of ART Initiation (R01 Clinical Trial Not Allowed)”. This application is built on collaborative research centered around the development and translation of small-molecule CD4-mimetic compounds (CD4mcs) as a cure strategy for HIV-1. CD4mcs synergize with CD4-induced (CD4i) Env antibodies (Abs) to render virus-infected cells highly vulnerable to antibody-mediated cellular cytotoxicity (ADCC) and clearance by immune effector cells. These CD4i Abs are present in most PLWH. This application leverages the recent discovery of a new class of indoline CD4mcs that displays remarkable improvements in antiviral potency and breadth against diverse primary HIV-1 strains. Treatment of HIV-1-infected humanized mice (hu-mice) with an indoline CD4mc and two types of CD4i Abs (anti-CoRBS/anti-Cluster A Abs) at the time of cART initiation resulted in a dramatic reduction in the size of the viral reservoir. This early CD4mc/Ab regimen enabled sustained virus control after analytical treatment interruption (ATI)! Furthermore, we identified a new family of Abs in PLWH that recognizes additional CD4i Env epitopes and that cooperate with indoline CD4mcs to significantly enhance ADCC. In line with these exciting discoveries, this application proposes three independent and interactive aims: Specific Aim 1 will investigate physiological variables (virologic parameters and timing of treatment) that facilitate effective reservoir elimination by CD4mc/Ab interventions in new-generation hu-mice that support immune effector cell function. In addition, multi-dimensional single-cell analytical techniques will identify the phenotypes, physiology and spatial organization of immune-effector cells and virus-infected cells in tissues harboring HIV-1 reservoirs. These studies will determine the factors related to CD4mc/Ab intervention that tip the balance in favor of durable viral control after ATI. Specific Aim 2 will formulate a highly effective CD4mc/Ab cocktail by screening plasma of PLWH to identify additional families of CD4iAbs with enhanced potency in mediating ADCC and evaluate them in hu-mice. Specific Aim 3 will systematically explore how the properties of the infecting viral Env influence reservoir establishment and susceptibility to elimination by the new indoline CD4mc/Ab cocktails in hu-mice. The outcome of these proof-of-principle studies is expected to inform the development of a CD4mc/Ab-based early intervention cure strategy for HIV-1.