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 R. Castillo-Menendez,Bruno Melillo,Daniel S. Terry,Amos B. Smith,Scott C. Blanchard,James B. Munro,Walther Mothes,Andrés Finzi,Joseph Sodroski +12 more
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TLDR
Increased sampling of state 2 is an Env conformation on the virus entry pathway 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.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.read more
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Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET
Maolin Lu,Xiaochu Ma,Luis R. Castillo-Menendez,Jason Gorman,Nirmin Alsahafi,Nirmin Alsahafi,Utz Ermel,Daniel S. Terry,Michael Chambers,Dongjun Peng,Baoshan Zhang,Tongqing Zhou,Nick Reichard,Kevin Wang,Jonathan R. Grover,Brennan P. Carman,Matthew R. Gardner,Ivana Nikić-Spiegel,Akihiro Sugawara,James Arthos,Edward A. Lemke,Edward A. Lemke,Amos B. Smith,Michael Farzan,Cameron F. Abrams,James B. Munro,Adrian B. McDermott,Andrés Finzi,Andrés Finzi,Peter D. Kwong,Scott C. Blanchard,Joseph Sodroski,Walther Mothes +32 more
TL;DR: Comparing the conformational states of Env trimers used for structural studies with native Env on intact virus finds that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3.
Journal ArticleDOI
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations.
Xiaochu Ma,Maolin Lu,Jason Gorman,Daniel S. Terry,Xinyu Hong,Zhou Zhou,Hong Zhao,Roger B. Altman,James Arthos,Scott C. Blanchard,Peter D. Kwong,James B. Munro,Walther Mothes +12 more
TL;DR: HIV-1 entry into cells requires binding of the viral envelope glycoprotein (Env) to receptor CD4 and coreceptor, and the default intermediate configuration is asymmetric, with individual protomers adopting distinct conformations.
Journal ArticleDOI
Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529
Marie Pancera,Yen-Ting Lai,Tatsiana Bylund,Aliaksandr Druz,Sandeep Narpala,Sijy O'Dell,Arne Schön,Robert T. Bailer,Gwo-Yu Chuang,Hui Geng,Mark K. Louder,Reda Rawi,Djade I. Soumana,Andrés Finzi,Alon Herschhorn,Navid Madani,Joseph Sodroski,Ernesto Freire,David R. Langley,John R. Mascola,Adrian B. McDermott,Peter D. Kwong +21 more
TL;DR: Crystal structures at 3.8-Å resolution are reported of HIV-1-Env trimer with BMS-378806 and its derivative, B MS-626529, and mechanisms whereby these small-molecule leads inhibit CD4–induced structural changes in Env are illuminated.
Journal ArticleDOI
An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity.
Nirmin Alsahafi,Nordine Bakouche,Mohsen Kazemi,Jonathan Richard,Shilei Ding,Sudipta Bhattacharyya,Durba Das,Sai Priya Anand,Jérémie Prévost,William D. Tolbert,Hong Lu,Halima Medjahed,Gabrielle Gendron-Lepage,Gloria G. Delgado,Sharon Kirk,Bruno Melillo,Walther Mothes,Joseph Sodroski,Amos B. Smith,Daniel Kaufmann,Xueling Wu,Marzena Pazgier,Isabelle Rouiller,Andrés Finzi,Andrés Finzi,James B. Munro +25 more
TL;DR: An asymmetric Env conformation (State 2A) is uncovered recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC, which may represent approaches to fight HIV-1 infection.
Journal ArticleDOI
Inhibitors of HIV-1 Attachment: The Discovery and Development of Temsavir and its Prodrug Fostemsavir.
Nicholas A. Meanwell,Mark Krystal,Beata Nowicka-Sans,David R. Langley,David A. Conlon,Martin D. Eastgate,Dennis M. Grasela,Peter Timmins,Tao Wang,John F. Kadow +9 more
TL;DR: The structure-activity and structure-liability studies leading to the discovery of temsavir and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials are summarized.
References
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HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein–Coupled Receptor
TL;DR: Fusin this article is a putative G protein-coupled receptor with seven transmembrane segments, which enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and infection.
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Journal ArticleDOI
HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.
Tatjana Dragic,Virginia M. Litwin,Graham P. Allaway,Scott R. Martin,Yaoxing Huang,Kirsten A. Nagashima,Charmagne Cayanan,Paul J. Maddon,Richard A. Koup,John P. Moore,William A. Paxton +10 more
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