D-109 Understanding and Exploiting the Conformational States of the HIV-1 Envelope Glycoprotein Trimer. (March 2017)

• Record Type: Journal Article
• Authors: Sodroski, Joseph
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 74(2017)Supplement 3
• Publication Date: 2017-03
• Subjects: AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/01.qai.0000513845.33068.8f
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : Primary human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimers typically exist in a metastable closed conformation (state 1). Binding the CD4 receptor triggers extensive conformational changes in Env, allowing Env to mediate virus entry. We investigated the conformations of the HIV-1JR-FL Env on the virus entry pathway. We identified specific gp120 residues that restrain Env in state 1. Alteration of these restraining residues destabilized state 1, allowing Env to populate a functional conformation (state 2) intermediate between state 1 and the full CD4-bound state (state 3). Increased state 2 occupancy was associated with lower energy barriers between the states. State 2 was an obligate intermediate for all transitions between state 1 and state 3. The unrestrained, state-2-enriched Envs required lower CD4 concentrations to trigger virus entry and exhibited an improved ability to infect primary macrophages. These Envs were resistant to several broadly neutralizing antibodies and small-molecule inhibitors. Thus, state 2 is an Env conformation on the virus entry pathway; sampling state 2 increases the adaptability of HIV-1 to different host cell receptor levels and immune environments. Small-molecule CD4-mimetic compounds bind gp120 and block CD4 binding. CD4-mimetic compounds prematurely trigger conformational transitions in Env, driving Env from State 1 to downstream conformations, leading to irreversible inactivation at a higher stoichiometry. At lower stoichiometry, CD4-mimetic compounds sensitize HIV-1 to neutralization and ADCC mediated by readily elicited antibodies. The potential application of HIV-1 sensitization to protection against virus transmission will be discussed.