Release of GP120 restraints leads to an entry-competent intermediate state of the HIV-1 envelope glycoproteins

Alon Herschhorn, Xiaochu Ma, Christopher Gu, John D. Ventura, Luis Castillo-Menendez, Bruno Melillo, Daniel S. Terry, Amos B. Smith, Scott C. Blanchard, James B. Munro, Walther Mothes, Andrés Finzi, Joseph Sodroski

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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. IMPORTANCE 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.

Original languageEnglish (US)
Article numbere01598-16
JournalmBio
Volume7
Issue number5
DOIs
StatePublished - Sep 1 2016

Bibliographical note

Funding Information:
This work, including the efforts of Joseph G. Sodroski, was funded by HHS | National Institutes of Health (NIH) (AI24755). This work, including the efforts of Joseph G. Sodroski, was funded by HHS | National Institutes of Health (NIH) (GM56550). This work, including the efforts of Joseph G. Sodroski, was funded by HHS | National Institutes of Health (NIH) (AI100645). This work, including the efforts of Walther Mothes, was funded by HHS | National Institutes of Health (NIH) (GM116654). This work, including the efforts of Walther Mothes, was funded by HHS | National Institutes of Health (NIH) (GM56550). This work, including the efforts of Scott Blanchard, was funded by HHS | National Institutes of Health (NIH) (GM098859). This work, including the efforts of James Munro, was funded by HHS | National Institutes of Health (NIH) (AI116262). This work, including the efforts of Alon Herschhorn, was funded by amfAR, The Foundation for AIDS Research (amfAR) (10850-53-RKNT and 109285-58-RKVA). This work, including the efforts of Andres Finzi, was funded by Canada Research Chairs (Chaires de recherche du Canada).

Publisher Copyright:
© 2016 Herschhorn et al.

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