Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

Tinashe E. Nyanhete; Robert J. Edwards; Celia C. LaBranche; Katayoun Mansouri; Amanda Eaton; S. Moses Dennison; Kevin O. Saunders; Derrick Goodman; Katarzyna Janowska; Rachel L. Spreng; Lu Zhang; Sarah V. Mudrak; Thomas J. Hope; Bhavna Hora; Todd Bradley; Ivelin S. Georgiev; David C. Montefiori; Priyamvada Acharya; Georgia D. Tomaras

doi:10.3389/fimmu.2021.670561

Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

Tinashe E. Nyanhete, Robert J. Edwards, Celia C. LaBranche, Katayoun Mansouri, Amanda Eaton, S. Moses Dennison, Kevin O. Saunders, Derrick Goodman, Katarzyna Janowska, Rachel L. Spreng, Lu Zhang, Sarah V. Mudrak, Thomas J. Hope, Bhavna Hora, Todd Bradley, Ivelin S. Georgiev, David C. Montefiori, Priyamvada Acharya, Georgia D. Tomaras^*

^*Corresponding author for this work

Cell & Developmental Biology

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

3 Scopus citations

Abstract

Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.

Original language	English (US)
Article number	670561
Journal	Frontiers in immunology
Volume	12
DOIs	https://doi.org/10.3389/fimmu.2021.670561
State	Published - Dec 23 2021

Funding

This work was supported by the NIH/NIAID-funded 1P01A1120756, R01AI145687, R01AI131722, R56AI052779, Center for HIV-1/AIDS Vaccine Immunology and Immunogen Discovery (Grant UMI-AI100645), and the Center for AIDS Research (P30 AI064518). We thank Tom Denny and the Immunology Quality Assessment Program for viral load analyses (NIH/NIAID 272201400014C). We thank Guido Ferrari for helpful discussions; Mike Archibald, Milite Abraha, LaTonya Williams, Jonathan Li, Richard Huntwork, Matthew Tay, and Heidi Register for their technical expertise and advice; Mark Sampson for help with figures; Drs. Coleen Cunningham and John Bartlett of the Duke CFAR Clinical Core, Clinical Core Staff (Stuart Carr and Sunita Patil) and the patients, physicians, and staff of the Duke Adult Infectious Diseases Clinic (Gary Cox, Nathan Thielman, Cameron Wolfe, Elizabeth Livingston, Brianna Norton, Kristen Dicks, Mehri McKellar, Vivian Chu, Jason Stout, and Ann Mosher) for virus controller patient recruitment.

Keywords

CD4-binding site antibodies
HIV-1 Virus Controllers
antibody-dependent cellular phagocytosis (ADCP)
broadly neutralizing antibodies
negative-stain electron microscopy
neutralization fingerprinting assay

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fimmu.2021.670561

Cite this

Nyanhete, T. E., Edwards, R. J., LaBranche, C. C., Mansouri, K., Eaton, A., Dennison, S. M., Saunders, K. O., Goodman, D., Janowska, K., Spreng, R. L., Zhang, L., Mudrak, S. V., Hope, T. J., Hora, B., Bradley, T., Georgiev, I. S., Montefiori, D. C., Acharya, P., & Tomaras, G. D. (2021). Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers. Frontiers in immunology, 12, Article 670561. https://doi.org/10.3389/fimmu.2021.670561

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title = "Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers",

abstract = "Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy na{\"i}ve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.",

keywords = "CD4-binding site antibodies, HIV-1 Virus Controllers, antibody-dependent cellular phagocytosis (ADCP), broadly neutralizing antibodies, negative-stain electron microscopy, neutralization fingerprinting assay",

author = "Nyanhete, {Tinashe E.} and Edwards, {Robert J.} and LaBranche, {Celia C.} and Katayoun Mansouri and Amanda Eaton and Dennison, {S. Moses} and Saunders, {Kevin O.} and Derrick Goodman and Katarzyna Janowska and Spreng, {Rachel L.} and Lu Zhang and Mudrak, {Sarah V.} and Hope, {Thomas J.} and Bhavna Hora and Todd Bradley and Georgiev, {Ivelin S.} and Montefiori, {David C.} and Priyamvada Acharya and Tomaras, {Georgia D.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 Nyanhete, Edwards, LaBranche, Mansouri, Eaton, Dennison, Saunders, Goodman, Janowska, Spreng, Zhang, Mudrak, Hope, Hora, Bradley, Georgiev, Montefiori, Acharya and Tomaras.",

year = "2021",

month = dec,

day = "23",

doi = "10.3389/fimmu.2021.670561",

language = "English (US)",

volume = "12",

journal = "Frontiers in immunology",

issn = "1664-3224",

publisher = "Frontiers Media S. A.",

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Nyanhete, TE, Edwards, RJ, LaBranche, CC, Mansouri, K, Eaton, A, Dennison, SM, Saunders, KO, Goodman, D, Janowska, K, Spreng, RL, Zhang, L, Mudrak, SV, Hope, TJ, Hora, B, Bradley, T, Georgiev, IS, Montefiori, DC, Acharya, P & Tomaras, GD 2021, 'Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers', Frontiers in immunology, vol. 12, 670561. https://doi.org/10.3389/fimmu.2021.670561

TY - JOUR

T1 - Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

AU - Nyanhete, Tinashe E.

AU - Edwards, Robert J.

AU - LaBranche, Celia C.

AU - Mansouri, Katayoun

AU - Eaton, Amanda

AU - Dennison, S. Moses

AU - Saunders, Kevin O.

AU - Goodman, Derrick

AU - Janowska, Katarzyna

AU - Spreng, Rachel L.

AU - Zhang, Lu

AU - Mudrak, Sarah V.

AU - Hope, Thomas J.

AU - Hora, Bhavna

AU - Bradley, Todd

AU - Georgiev, Ivelin S.

AU - Montefiori, David C.

AU - Acharya, Priyamvada

AU - Tomaras, Georgia D.

N1 - Publisher Copyright: Copyright © 2021 Nyanhete, Edwards, LaBranche, Mansouri, Eaton, Dennison, Saunders, Goodman, Janowska, Spreng, Zhang, Mudrak, Hope, Hora, Bradley, Georgiev, Montefiori, Acharya and Tomaras.

PY - 2021/12/23

Y1 - 2021/12/23

N2 - Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.

AB - Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.

KW - CD4-binding site antibodies

KW - HIV-1 Virus Controllers

KW - antibody-dependent cellular phagocytosis (ADCP)

KW - broadly neutralizing antibodies

KW - negative-stain electron microscopy

KW - neutralization fingerprinting assay

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U2 - 10.3389/fimmu.2021.670561

DO - 10.3389/fimmu.2021.670561

M3 - Article

C2 - 35003053

AN - SCOPUS:85122365479

SN - 1664-3224

VL - 12

JO - Frontiers in immunology

JF - Frontiers in immunology

M1 - 670561

ER -

Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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