Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) envelope (Env) trimer evades antibody recognition by adopting a closed prefusion conformation. Here, we show that two conserved tyrosines (Y173, Y177) within the second variable (V2) loop of the gp120 Env glycoprotein are key regulators of the...

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Autores principales: Christina Guzzo, Peng Zhang, Qingbo Liu, Alice L. Kwon, Ferzan Uddin, Alexandra I. Wells, Hana Schmeisser, Raffaello Cimbro, Jinghe Huang, Nicole Doria-Rose, Stephen D. Schmidt, Michael A. Dolan, Mark Connors, John R. Mascola, Paolo Lusso
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Publicado: American Society for Microbiology 2018
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spelling oai:doaj.org-article:4219b1d66dad426da628082e667f09a52021-11-15T15:52:19ZStructural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation10.1128/mBio.00955-182150-7511https://doaj.org/article/4219b1d66dad426da628082e667f09a52018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00955-18https://doaj.org/toc/2150-7511ABSTRACT The human immunodeficiency virus type 1 (HIV-1) envelope (Env) trimer evades antibody recognition by adopting a closed prefusion conformation. Here, we show that two conserved tyrosines (Y173, Y177) within the second variable (V2) loop of the gp120 Env glycoprotein are key regulators of the closed, antibody-protected state of the trimer by establishing intramolecular interaction with the base of the third variable (V3) loop. Mutation of Y177 and/or Y173 to phenylalanine or alanine dramatically altered the susceptibility of diverse HIV-1 strains to neutralization, increasing sensitivity to weakly and nonneutralizing antibodies directed against diverse Env regions, consistent with the adoption of an open trimer configuration. Conversely, potent broadly neutralizing antibodies (bNAbs) against different supersites of HIV-1 vulnerability exhibited reduced potency against V2 loop tyrosine mutants, consistent with their preferential targeting of the closed trimer. Mutation of V3 loop residues predicted to interact with the V2 loop tyrosines yielded a similar neutralization phenotype. Sera from chronically HIV-1-infected patients contained very high titers of antibodies capable of neutralizing V2 loop tyrosine mutants but not wild-type viruses, indicating that the bulk of antibodies produced in infected hosts are unable to penetrate the protective shield of the closed trimer. These results identify the tyrosine-mediated V2-V3 loop complex at the trimer apex as a key structural constraint that facilitates HIV-1 evasion from the bulk of host antibodies. IMPORTANCE The extraordinary ability of human immunodeficiency virus type 1 (HIV-1) to evade host immunity represents a major obstacle to the development of a protective vaccine. Thus, elucidating the mechanisms whereby HIV-1 protects its external envelope (Env), which is the sole target of virus-neutralizing antibodies, is an essential step toward vaccine design. We identified a key structural element that maintains the HIV-1 Env trimer in a closed, antibody-resistant conformation. A major role is played by two conserved tyrosines at the apex of the Env spike, whose mutation causes a global opening of the trimer structure, exposing multiple concealed targets for neutralizing antibodies. We also found that HIV-infected individuals produce very large amounts of antibodies that neutralize the open Env form; however, the bulk of these antibodies are unable to penetrate the tight defensive shield of the native virus. This work may help to devise new strategies to overcome the viral defensive mechanisms and facilitate the development of an effective HIV-1 vaccine.Christina GuzzoPeng ZhangQingbo LiuAlice L. KwonFerzan UddinAlexandra I. WellsHana SchmeisserRaffaello CimbroJinghe HuangNicole Doria-RoseStephen D. SchmidtMichael A. DolanMark ConnorsJohn R. MascolaPaolo LussoAmerican Society for Microbiologyarticlehuman immunodeficiency virusimmune evasionneutralizing antibodiesviral envelopeMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution DOAJ
collection DOAJ
language EN
topic human immunodeficiency virus
immune evasion
neutralizing antibodies
viral envelope
Microbiology
QR1-502
spellingShingle human immunodeficiency virus
immune evasion
neutralizing antibodies
viral envelope
Microbiology
QR1-502
Christina Guzzo
Peng Zhang
Qingbo Liu
Alice L. Kwon
Ferzan Uddin
Alexandra I. Wells
Hana Schmeisser
Raffaello Cimbro
Jinghe Huang
Nicole Doria-Rose
Stephen D. Schmidt
Michael A. Dolan
Mark Connors
John R. Mascola
Paolo Lusso
Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
description ABSTRACT The human immunodeficiency virus type 1 (HIV-1) envelope (Env) trimer evades antibody recognition by adopting a closed prefusion conformation. Here, we show that two conserved tyrosines (Y173, Y177) within the second variable (V2) loop of the gp120 Env glycoprotein are key regulators of the closed, antibody-protected state of the trimer by establishing intramolecular interaction with the base of the third variable (V3) loop. Mutation of Y177 and/or Y173 to phenylalanine or alanine dramatically altered the susceptibility of diverse HIV-1 strains to neutralization, increasing sensitivity to weakly and nonneutralizing antibodies directed against diverse Env regions, consistent with the adoption of an open trimer configuration. Conversely, potent broadly neutralizing antibodies (bNAbs) against different supersites of HIV-1 vulnerability exhibited reduced potency against V2 loop tyrosine mutants, consistent with their preferential targeting of the closed trimer. Mutation of V3 loop residues predicted to interact with the V2 loop tyrosines yielded a similar neutralization phenotype. Sera from chronically HIV-1-infected patients contained very high titers of antibodies capable of neutralizing V2 loop tyrosine mutants but not wild-type viruses, indicating that the bulk of antibodies produced in infected hosts are unable to penetrate the protective shield of the closed trimer. These results identify the tyrosine-mediated V2-V3 loop complex at the trimer apex as a key structural constraint that facilitates HIV-1 evasion from the bulk of host antibodies. IMPORTANCE The extraordinary ability of human immunodeficiency virus type 1 (HIV-1) to evade host immunity represents a major obstacle to the development of a protective vaccine. Thus, elucidating the mechanisms whereby HIV-1 protects its external envelope (Env), which is the sole target of virus-neutralizing antibodies, is an essential step toward vaccine design. We identified a key structural element that maintains the HIV-1 Env trimer in a closed, antibody-resistant conformation. A major role is played by two conserved tyrosines at the apex of the Env spike, whose mutation causes a global opening of the trimer structure, exposing multiple concealed targets for neutralizing antibodies. We also found that HIV-infected individuals produce very large amounts of antibodies that neutralize the open Env form; however, the bulk of these antibodies are unable to penetrate the tight defensive shield of the native virus. This work may help to devise new strategies to overcome the viral defensive mechanisms and facilitate the development of an effective HIV-1 vaccine.
format article
author Christina Guzzo
Peng Zhang
Qingbo Liu
Alice L. Kwon
Ferzan Uddin
Alexandra I. Wells
Hana Schmeisser
Raffaello Cimbro
Jinghe Huang
Nicole Doria-Rose
Stephen D. Schmidt
Michael A. Dolan
Mark Connors
John R. Mascola
Paolo Lusso
author_facet Christina Guzzo
Peng Zhang
Qingbo Liu
Alice L. Kwon
Ferzan Uddin
Alexandra I. Wells
Hana Schmeisser
Raffaello Cimbro
Jinghe Huang
Nicole Doria-Rose
Stephen D. Schmidt
Michael A. Dolan
Mark Connors
John R. Mascola
Paolo Lusso
author_sort Christina Guzzo
title Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
title_short Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
title_full Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
title_fullStr Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
title_full_unstemmed Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
title_sort structural constraints at the trimer apex stabilize the hiv-1 envelope in a closed, antibody-protected conformation
publisher American Society for Microbiology
publishDate 2018
url https://doaj.org/article/4219b1d66dad426da628082e667f09a5
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