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 Gabrielle Ortega Delgado; Sharon Kirk; Bruno Melillo; Walther Mothes; Joseph Sodroski; Amos B. Smith; Daniel E. Kaufmann; Xueling Wu; Marzena Pazgier; Isabelle Rouiller; Andrés Finzi; James B. Munro

doi:10.1016/j.chom.2019.03.002

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 Gabrielle Ortega Delgado, Sharon Kirk, Bruno Melillo, Walther Mothes, Joseph Sodroski, Amos B. Smith, Daniel E. KaufmannXueling Wu, Marzena Pazgier, Isabelle Rouiller^*, Andrés Finzi, James B. Munro

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

The HIV-1 envelope glycoprotein (Env) (gp120-gp41) ₃ is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 ⁺ T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity.

Original language	English
Pages (from-to)	578-587.e5
Journal	Cell Host and Microbe
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2019.03.002
State	Published - 10 Apr 2019
Externally published	Yes

Keywords

17b
A32
ADCC
CD4i Abs
HIV-1
State 2A
cryo-EM
envelope glycoproteins
smFRET

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10.1016/j.chom.2019.03.002

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Alsahafi, N., Bakouche, N., Kazemi, M., Richard, J., Ding, S., Bhattacharyya, S., Das, D., Anand, S. P., Prévost, J., Tolbert, W. D., Lu, H., Medjahed, H., Gendron-Lepage, G., Ortega Delgado, G. G., Kirk, S., Melillo, B., Mothes, W., Sodroski, J., Smith, A. B., ... Munro, J. B. (2019). An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity. Cell Host and Microbe, 25(4), 578-587.e5. https://doi.org/10.1016/j.chom.2019.03.002

@article{5e24422acb874b7fa4a411736d5da386,

title = "An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity",

abstract = " The HIV-1 envelope glycoprotein (Env) (gp120-gp41) 3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 + T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity.",

keywords = "17b, A32, ADCC, CD4i Abs, HIV-1, State 2A, cryo-EM, envelope glycoproteins, smFRET",

author = "Nirmin Alsahafi and Nordine Bakouche and Mohsen Kazemi and Jonathan Richard and Shilei Ding and Sudipta Bhattacharyya and Durba Das and Anand, {Sai Priya} and J{\'e}r{\'e}mie Pr{\'e}vost and Tolbert, {William D.} and Hong Lu and Halima Medjahed and Gabrielle Gendron-Lepage and {Ortega Delgado}, {Gloria Gabrielle} and Sharon Kirk and Bruno Melillo and Walther Mothes and Joseph Sodroski and Smith, {Amos B.} and Kaufmann, {Daniel E.} and Xueling Wu and Marzena Pazgier and Isabelle Rouiller and Andr{\'e}s Finzi and Munro, {James B.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = apr,

day = "10",

doi = "10.1016/j.chom.2019.03.002",

language = "English",

volume = "25",

pages = "578--587.e5",

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Alsahafi, N, Bakouche, N, Kazemi, M, Richard, J, Ding, S, Bhattacharyya, S, Das, D, Anand, SP, Prévost, J, Tolbert, WD, Lu, H, Medjahed, H, Gendron-Lepage, G, Ortega Delgado, GG, Kirk, S, Melillo, B, Mothes, W, Sodroski, J, Smith, AB, Kaufmann, DE, Wu, X, Pazgier, M, Rouiller, I, Finzi, A & Munro, JB 2019, 'An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity', Cell Host and Microbe, vol. 25, no. 4, pp. 578-587.e5. https://doi.org/10.1016/j.chom.2019.03.002

TY - JOUR

T1 - An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

AU - Alsahafi, Nirmin

AU - Bakouche, Nordine

AU - Kazemi, Mohsen

AU - Richard, Jonathan

AU - Ding, Shilei

AU - Bhattacharyya, Sudipta

AU - Das, Durba

AU - Anand, Sai Priya

AU - Prévost, Jérémie

AU - Tolbert, William D.

AU - Lu, Hong

AU - Medjahed, Halima

AU - Gendron-Lepage, Gabrielle

AU - Ortega Delgado, Gloria Gabrielle

AU - Kirk, Sharon

AU - Melillo, Bruno

AU - Mothes, Walther

AU - Sodroski, Joseph

AU - Smith, Amos B.

AU - Kaufmann, Daniel E.

AU - Wu, Xueling

AU - Pazgier, Marzena

AU - Rouiller, Isabelle

AU - Finzi, Andrés

AU - Munro, James B.

PY - 2019/4/10

Y1 - 2019/4/10

N2 - The HIV-1 envelope glycoprotein (Env) (gp120-gp41) 3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 + T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity.

AB - The HIV-1 envelope glycoprotein (Env) (gp120-gp41) 3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 + T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity.

KW - 17b

KW - A32

KW - ADCC

KW - CD4i Abs

KW - HIV-1

KW - State 2A

KW - cryo-EM

KW - envelope glycoproteins

KW - smFRET

UR - http://www.scopus.com/inward/record.url?scp=85063391065&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2019.03.002

DO - 10.1016/j.chom.2019.03.002

M3 - Article

C2 - 30974085

AN - SCOPUS:85063391065

SN - 1931-3128

VL - 25

SP - 578-587.e5

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 4

ER -

An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

Abstract

Keywords

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