Exploring HIV-1 Env open conformations for therapeutic intervention

SUMMARY While current antiretroviral therapies (ART) control viral replication, they are unable to fully restore health or a normal immune status. ART-treated individuals experience several comorbidities, including increased cardiovascular disease, bone disorders, and cognitive impairment. Most importantly, therapy interruption leads to the re-emergence of viral replication and progression to AIDS. Therefore, new approaches aimed at eradicating or functionally curing HIV-1 infection are desperately needed. A promising strategy to eliminate latently infected cells after viral reactivation is the ability of immune cells to mediate antibody-dependent cellular cytotoxicity (ADCC). The RV144 HIV-1 vaccine trial in Thailand elicited only a modest 31.2% protective efficacy. Subsequent analyses indicated that this modest protection was correlated with the generation of IgG antibodies (Abs) with potent ADCC activity with low plasma IgA Abs specific to the HIV-1 envelope glycoprotein (Env). This suggests that ADCC may have contributed to the protection observed in the RV144 trial. But key unanswered questions prevent the development of new therapeutic or prophylactic approaches to specifically utilize the ADCC response: What are the structural and conformational features of Envs that are susceptible to ADCC responses? Specifically, what is the basis for the unique phenotype of Envs from the CRF01_AE subtype of HIV- 1, which predominates the Thai AIDS epidemic, and which are intrinsically susceptible to ADCC? Can this phenotype be induced in other Envs through therapeutic intervention? Answering these questions will prove crucial to the design of improved strategies to eliminate HIV-1-infected cells. The long-term goal of the research proposed here is to inform the development of new strategies for utilizing ADCC to eradicate HIV-1. Our central hypothesis is that the sensitivity of HIV-1 to ADCC is determined primarily by two factors: (1) Env conformation, which dictates the exposure of key epitopes targeted by Abs with potent effector function; and (2) properties of the Ab-antigen complex, including the orientation and flexibility of the Fc domain, which determines engagement with the Fc receptor (FcR). A corollary of this hypothesis is that the intrinsic propensity of Envs of different HIV- 1 subtypes to adopt open conformations contributes to their inherent susceptibility or resistance to ADCC. Determining the molecular basis for diverse ADCC sensitivity phenotypes will inform the development of strategies that manipulate Env conformation to stimulate ADCC. We will accomplish this goal using a multifaceted approach involving biophysical, structural, and virological interrogations.