Abstract
The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a “β strand” interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 873-883.e5 |
| Journal | Cell Host and Microbe |
| Volume | 25 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 12 2019 |
| Externally published | Yes |
Keywords
- ACS202
- AMC011
- HIV envelope glycoprotein
- VRC34.01
- X-ray crystallography
- broadly neutralizing antibody
- cryoelectron microscopy
- fusion peptide
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology
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In: Cell Host and Microbe, Vol. 25, No. 6, 12.06.2019, p. 873-883.e5.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies
AU - Yuan, Meng
AU - Cottrell, Christopher A.
AU - Ozorowski, Gabriel
AU - van Gils, Marit J.
AU - Kumar, Sonu
AU - Wu, Nicholas C.
AU - Sarkar, Anita
AU - Torres, Jonathan L.
AU - de Val, Natalia
AU - Copps, Jeffrey
AU - Moore, John P.
AU - Sanders, Rogier W.
AU - Ward, Andrew B.
AU - Wilson, Ian A.
N1 - We thank C.K. Wibmer, R.L. Stanfield, X. Zhu, X. Dai, B. Anderson, H.L. Turner, C. Bowman, Y. Hua, H. Tien, and W. Yu for support and technical expertise. This work was supported by the HIV Vaccine Research and Design (HIVRAD) program (P01 AI110657) (A.B.W. R.W.S, J.P.M. and I.A.W.), the International AIDS Vaccine Initiative Neutralizing Antibody Center, the Bill and Melinda Gates Foundation CAVD (OPP1115782, OPP1132237, and OPP1084519), and the European Union's Horizon 2020 research and innovation program under grant agreement no. 681137 (R.W.S.). C.A.C. is supported by the NIH F31 Ruth L. Kirschstein Predoctoral Award Al131873 and by the Achievement Rewards for College Scientists Foundation. R.W.S. is a recipient of a Vici fellowship from the Netherlands Organization for Scientific Research (NWO). G.O. and M.J.v.G. are supported by amfAR Mathilde Krim Fellowships in Basic Biomedical Research grant no. 109718-63-RKNT and grant no. 109514-61-RKVA, respectively. X-ray datasets were collected at the GM/CA@APS-23ID-B beamline, which has been funded in whole or in part with federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source (APS), a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The Amsterdam Cohort Studies (ACS) on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, and the Jan van Goyen Clinic, is part of The Netherlands HIV Monitoring Foundation and is financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment. Electron microscopy datasets were collected at the Scripps Research Institute. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIH or the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.Y. C.A.C. G.O. M.J.v.G. R.W.S. A.B.W. and I.A.W. designed the experiments with critical input from S.K. N.C.W. and J.P.M. Structural studies were performed by M.Y. C.A.C. N.d.V. and G.O.; M.J.v.G. M.Y. and S.K. performed binding assays and neutralization assays; A.S. J.L.T. and J.C. produced reagents; and N.C.W. performed computational analyses. M.Y. and I.A.W. wrote the manuscript with input from all authors. The authors declare no competing interests. We thank C.K. Wibmer, R.L. Stanfield, X. Zhu, X. Dai, B. Anderson, H.L. Turner, C. Bowman, Y. Hua, H. Tien, and W. Yu for support and technical expertise. This work was supported by the HIV Vaccine Research and Design (HIVRAD) program ( P01 AI110657 ) (A.B.W., R.W.S, J.P.M., and I.A.W.), the International AIDS Vaccine Initiative Neutralizing Antibody Center , the Bill and Melinda Gates Foundation CAVD ( OPP1115782 , OPP1132237 , and OPP1084519 ), and the European Union’s Horizon 2020 research and innovation program under grant agreement no. 681137 (R.W.S.). C.A.C. is supported by the NIH F31 Ruth L. Kirschstein Predoctoral Award Al131873 and by the Achievement Rewards for College Scientists Foundation. R.W.S. is a recipient of a Vici fellowship from the Netherlands Organization for Scientific Research (NWO). G.O. and M.J.v.G. are supported by amfAR Mathilde Krim Fellowships in Basic Biomedical Research grant no. 109718-63-RKNT and grant no. 109514-61-RKVA , respectively. X-ray datasets were collected at the GM/CA@APS-23ID-B beamline, which has been funded in whole or in part with federal funds from the National Cancer Institute ( ACB-12002 ) and the National Institute of General Medical Sciences ( AGM-12006 ). This research used resources of the Advanced Photon Source (APS), a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The Amsterdam Cohort Studies (ACS) on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, and the Jan van Goyen Clinic, is part of The Netherlands HIV Monitoring Foundation and is financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment . Electron microscopy datasets were collected at the Scripps Research Institute. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIH or the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank C.K. Wibmer, R.L. Stanfield, X. Zhu, X. Dai, B. Anderson, H.L. Turner, C. Bowman, Y. Hua, H. Tien, and W. Yu for support and technical expertise. This work was supported by the HIV Vaccine Research and Design (HIVRAD)program (P01 AI110657)(A.B.W. R.W.S, J.P.M. and I.A.W.), the International AIDS Vaccine Initiative Neutralizing Antibody Center, the Bill and Melinda Gates Foundation CAVD (OPP1115782, OPP1132237, and OPP1084519), and the European Union's Horizon 2020 research and innovation program under grant agreement no. 681137 (R.W.S.). C.A.C. is supported by the NIH F31 Ruth L. Kirschstein Predoctoral Award Al131873 and by the Achievement Rewards for College Scientists Foundation. R.W.S. is a recipient of a Vici fellowship from the Netherlands Organization for Scientific Research (NWO). G.O. and M.J.v.G. are supported by amfAR Mathilde Krim Fellowships in Basic Biomedical Research grant no. 109718-63-RKNT and grant no. 109514-61-RKVA, respectively. X-ray datasets were collected at the GM/CA@APS-23ID-B beamline, which has been funded in whole or in part with federal funds from the National Cancer Institute (ACB-12002)and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source (APS), a US Department of Energy (DOE)Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The Amsterdam Cohort Studies (ACS)on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, and the Jan van Goyen Clinic, is part of The Netherlands HIV Monitoring Foundation and is financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment. Electron microscopy datasets were collected at the Scripps Research Institute. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIH or the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M.Y. C.A.C. G.O. M.J.v.G. R.W.S. A.B.W. and I.A.W. designed the experiments with critical input from S.K. N.C.W. and J.P.M. Structural studies were performed by M.Y. C.A.C. N.d.V. and G.O.; M.J.v.G. M.Y. and S.K. performed binding assays and neutralization assays; A.S. J.L.T. and J.C. produced reagents; and N.C.W. performed computational analyses. M.Y. and I.A.W. wrote the manuscript with input from all authors. The authors declare no competing interests.
PY - 2019/6/12
Y1 - 2019/6/12
N2 - The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a “β strand” interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
AB - The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a “β strand” interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
KW - ACS202
KW - AMC011
KW - HIV envelope glycoprotein
KW - VRC34.01
KW - X-ray crystallography
KW - broadly neutralizing antibody
KW - cryoelectron microscopy
KW - fusion peptide
UR - http://www.scopus.com/inward/record.url?scp=85066277646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066277646&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2019.04.011
DO - 10.1016/j.chom.2019.04.011
M3 - Article
C2 - 31194940
AN - SCOPUS:85066277646
SN - 1931-3128
VL - 25
SP - 873-883.e5
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -