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MBio. 2016 Oct 25;7(5). pii: e01598-16. doi: 10.1128/mBio.01598-16.

Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins.

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Department of Immunology Cancer and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Immunology Cancer and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, USA.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts, USA.
Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology Université de Montréal, Montreal, Quebec, Canada; Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.


Primary human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimers [(gp120/gp41)3] typically exist in a metastable closed conformation (state 1). Binding the CD4 receptor triggers Env to undergo extensive conformational changes to mediate virus entry. 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. State 2-enriched Envs required lower CD4 concentrations to trigger virus entry and more efficiently infected cells expressing low levels of CD4. 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. Our results provide new insights into the conformational regulation of HIV-1 entry.


The envelope glycoproteins (Env) of HIV-1 mediate virus entry and are the sole targets of neutralizing antibodies. Understanding the way that Env promotes HIV-1 entry can expedite drug and vaccine development. By destabilizing Env, we found that it assumes an intermediate state that is functional and obligate for transitions to entry-competent conformations. Increased sampling of this state enhances the ability of HIV-1 to infect cells that express low levels of the CD4 receptor and allows the virus to evade neutralizing antibodies and small-molecule inhibitors. These findings provide new mechanistic insights into the function and inhibition of HIV-1 Env and will contribute to ongoing therapeutic and prevention efforts to combat HIV-1.

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