TY - JOUR
T1 - Near-pan-neutralizing, plasma deconvoluted antibody N49P6 mimics host receptor CD4 in its quaternary interactions with the HIV-1 envelope trimer
AU - Tolbert, William D.
AU - Nguyen, Dung N.
AU - Tehrani, Zahra Rikhtegaran
AU - Sajadi, Mohammad M.
AU - Pazgier, Marzena
N1 - Funding Information:
by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the contents of this publication are solely the responsibility of the authors.
Funding Information:
for this study was provided by National Institutes of Health grants R01 AI116274 to M.P.; R01 AI129769 to M.P.; R01 AI147870, IBX004525, and OPP1197311 to M.M.S.; and P01 AI120756 to M.P. and Georgia Tomaras. Use of the Stanford Synchrotron Radiation Light Source, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the contents of this publication are solely the responsibility of the authors. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, U.S. Army, the Department of Defense, or the U.S. Government. We declare that we have no competing interests. W.D.T., D.N.N., and M.P. designed, performed research, and analyzed the data; Z.R.T. and M.M.S. isolated N49P6 antibody and performed neutralization assays; W.D.T., D.N.N., andM.P.wrotethemanuscript;andallauthorsprovidedcommentsorrevisions.
Funding Information:
Funding for this study was provided by National Institutes of Health grants R01 AI116274 to M.P.; R01 AI129769 to M.P.; R01 AI147870, IBX004525, and OPP1197311 to M.M.S.; and P01 AI120756 to M.P. and Georgia Tomaras. Use of the Stanford Synchrotron Radiation Light Source, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported
Publisher Copyright:
© 2021, American Society for Microbiology. All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - The first step in HIV-1 entry is the attachment of the envelope (Env) trimer to target cell CD4. As such, the CD4-binding site (CD4bs) remains one of the few univer-sally accessible sites for antibodies (Abs). We recently described a method of isolating Abs directly from the circulating plasma and described a panel of broadly neutralizing Abs (bnAbs) from an HIV-1 “elite neutralizer” referred to as patient N49 (N49 Ab lineage [M.M.Sajadi,A.Dashti,Z.R.Tehrani,W.D.Tolbert,etal.,Cell173:1783–1795.e14, 2018, https://doi.org/10.1016/j.cell.2018.03.061]). Here, we describe the molecular details of antigen recognition by N49P6, an Ab of the N49 lineage that recapitulates most of the neutralization breadth and potency of the donor’s plasmaIgG.Ourstudiesdoneinthe context of monomeric and trimeric antigens indicate that N49P6 combines many characteristics of known CD4bs-specific bnAbs with features that are unique to the N49 Ab lineage to achieve its remarkable neutralization breadth. These include the omission of the CD4 Phe43 cavity and dependence instead on interactions with highly conserved gp120 inner domain layer 3. Interestingly, when bound to BG505 SOSIP, N49P6 closely mimics the initial contact of host receptor CD4 to the adjacent promoter of the HIV-1 Env trimer to lock the trimer in the closed conformation. Altogether, N49P6 defines a new class of near-pan-neutralizing, plasma deconvoluted CD4bs Abs that we refer to as the N49P series. The details of the mechanisms of action of this new Ab class pave the way for the next generation of HIV-1 bnAbs that can be used as vaccine components of therapeutics. IMPORTANCE Binding to target cell CD4 is the first crucial step required for HIV-1 infection. Thus, the CD4-binding site (CD4bs) is one of the most accessible sites for antibodies (Abs). However, due to steric constraints, only a few Abs are capable of targeting this site. Here, we show that the exceptional neutralization breadth and potency of N49P6, a near-pan-neutralizing Ab targeting the CD4bs isolated from the plasma of an HIV-1 “elite neutralizer,” patient N49, are due to its signature combination of more typical CD4bs Ab-binding characteristics with unique interactions with the highly conserved gp120 inner domain. In addition, we also present a structural analysis of N49P6 in complex with the BG505 SOSIP trimer to show that N49P6 exhibits remarkable breadth in part by mimicking CD4’s quaternary interaction with the neighboring gp120 protomer. In its mode of antigen interaction, N49P6 is unique and represents a new class of CD4bs-specific bnAbs.
AB - The first step in HIV-1 entry is the attachment of the envelope (Env) trimer to target cell CD4. As such, the CD4-binding site (CD4bs) remains one of the few univer-sally accessible sites for antibodies (Abs). We recently described a method of isolating Abs directly from the circulating plasma and described a panel of broadly neutralizing Abs (bnAbs) from an HIV-1 “elite neutralizer” referred to as patient N49 (N49 Ab lineage [M.M.Sajadi,A.Dashti,Z.R.Tehrani,W.D.Tolbert,etal.,Cell173:1783–1795.e14, 2018, https://doi.org/10.1016/j.cell.2018.03.061]). Here, we describe the molecular details of antigen recognition by N49P6, an Ab of the N49 lineage that recapitulates most of the neutralization breadth and potency of the donor’s plasmaIgG.Ourstudiesdoneinthe context of monomeric and trimeric antigens indicate that N49P6 combines many characteristics of known CD4bs-specific bnAbs with features that are unique to the N49 Ab lineage to achieve its remarkable neutralization breadth. These include the omission of the CD4 Phe43 cavity and dependence instead on interactions with highly conserved gp120 inner domain layer 3. Interestingly, when bound to BG505 SOSIP, N49P6 closely mimics the initial contact of host receptor CD4 to the adjacent promoter of the HIV-1 Env trimer to lock the trimer in the closed conformation. Altogether, N49P6 defines a new class of near-pan-neutralizing, plasma deconvoluted CD4bs Abs that we refer to as the N49P series. The details of the mechanisms of action of this new Ab class pave the way for the next generation of HIV-1 bnAbs that can be used as vaccine components of therapeutics. IMPORTANCE Binding to target cell CD4 is the first crucial step required for HIV-1 infection. Thus, the CD4-binding site (CD4bs) is one of the most accessible sites for antibodies (Abs). However, due to steric constraints, only a few Abs are capable of targeting this site. Here, we show that the exceptional neutralization breadth and potency of N49P6, a near-pan-neutralizing Ab targeting the CD4bs isolated from the plasma of an HIV-1 “elite neutralizer,” patient N49, are due to its signature combination of more typical CD4bs Ab-binding characteristics with unique interactions with the highly conserved gp120 inner domain. In addition, we also present a structural analysis of N49P6 in complex with the BG505 SOSIP trimer to show that N49P6 exhibits remarkable breadth in part by mimicking CD4’s quaternary interaction with the neighboring gp120 protomer. In its mode of antigen interaction, N49P6 is unique and represents a new class of CD4bs-specific bnAbs.
KW - CD4-binding site
KW - HIV
KW - N49P lineage
KW - Near-pan-neutralizing
KW - Neutralizing antibodies
UR - http://www.scopus.com/inward/record.url?scp=85114101126&partnerID=8YFLogxK
U2 - 10.1128/mBio.01274-21
DO - 10.1128/mBio.01274-21
M3 - Article
C2 - 34281393
AN - SCOPUS:85114101126
SN - 2161-2129
VL - 12
JO - mBio
JF - mBio
IS - 4
M1 - e01274-21
ER -