TY - JOUR
T1 - Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity
T2 - Structural Basis for Env Epitopes in the C11 Region
AU - Tolbert, William D.
AU - Gohain, Neelakshi
AU - Alsahafi, Nirmin
AU - Van, Verna
AU - Orlandi, Chiara
AU - Ding, Shilei
AU - Martin, Loïc
AU - Finzi, Andrés
AU - Lewis, George K.
AU - Ray, Krishanu
AU - Pazgier, Marzena
N1 - Funding Information:
We thank our IHV colleagues for outstanding support of the studies leading to the ideas presented here, specifically Dr. Anthony L. DeVico for his continued critical insights. This work was supported by NIH grants: NIAID R01 AI116274 to M.P., R01AI129769 to M.P. and A.F., NIGMS R01 GM117836 to K.R., NIAID P01 AI120756, and the Bill and Melinda Gates Foundation: OPP1033109 to G.K.L. This work was partially supported also by a CIHR foundation grant 352417 to A.F. who is supported by the Canada Research Chairs program. N.A. is the recipient of a King Abdullah scholarship for higher education from the Saudi Government. S.D. is a recipient of an FRQS postdoctoral Fellowship Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Crystallographic data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL), a Directorate of the SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the US Department of Energy Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the US Department of Energy Office of Biological and Environmental Research, by the NIH National Center for Research Resources, Biomedical Technology Program (P41RR001209), and by the National Institute of General Medical Sciences.
Funding Information:
We thank our IHV colleagues for outstanding support of the studies leading to the ideas presented here, specifically Dr. Anthony L. DeVico for his continued critical insights. This work was supported by NIH grants: NIAID R01 AI116274 to M.P., R01AI129769 to M.P. and A.F., NIGMS R01 GM117836 to K.R., NIAID P01 AI120756 , and the Bill and Melinda Gates Foundation : OPP1033109 to G.K.L. This work was partially supported also by a CIHR foundation grant 352417 to A.F. who is supported by the Canada Research Chairs program . N.A. is the recipient of a King Abdullah scholarship for higher education from the Saudi Government. S.D. is a recipient of an FRQS postdoctoral Fellowship Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Crystallographic data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL), a Directorate of the SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the US Department of Energy Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the US Department of Energy Office of Biological and Environmental Research , by the NIH National Center for Research Resources, Biomedical Technology Program ( P41RR001209 ), and by the National Institute of General Medical Sciences .
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11/7
Y1 - 2017/11/7
N2 - Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal “eighth strand” of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered β-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system. Tolbert at al. describe a crystal structure of Fabs of A32- and C11-like antibody bound to a single gp120 subunit. The C11-like antibody, N12-i3, recognizes a new eight-stranded β sandwich structure of gp120 that is formed at the late stage of HIV-1 entry.
AB - Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal “eighth strand” of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered β-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system. Tolbert at al. describe a crystal structure of Fabs of A32- and C11-like antibody bound to a single gp120 subunit. The C11-like antibody, N12-i3, recognizes a new eight-stranded β sandwich structure of gp120 that is formed at the late stage of HIV-1 entry.
KW - C11 epitope region
KW - C11-like antibody
KW - HIV-1 entry
KW - N12-i3 antibody
KW - antibody-dependent cellular cytotoxicity (ADCC)
KW - cluster A epitopes
KW - crystal structure
UR - http://www.scopus.com/inward/record.url?scp=85031804948&partnerID=8YFLogxK
U2 - 10.1016/j.str.2017.09.009
DO - 10.1016/j.str.2017.09.009
M3 - Article
C2 - 29056481
AN - SCOPUS:85031804948
SN - 0969-2126
VL - 25
SP - 1719-1731.e4
JO - Structure
JF - Structure
IS - 11
ER -