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Title: Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

Abstract

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope finemore » specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. In conclusion, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [4];  [1];  [1];  [1]
  1. Univ. of Maryland School of Medicine, Baltimore, MD (United States)
  2. Tulane Univ., New Orleans, LA (United States)
  3. Harvard Medical School, Boston, MA (United States)
  4. Profectus Biosciences, Inc., Baltimore, MD (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1136677
Report Number(s):
SLAC-REPRINT-2014-212
Journal ID: ISSN 0027-8424
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 110; Journal Issue: 1; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Guan, Yongjun, Pazgier, Marzena, Sajadi, Mohammad M., Kamin-Lewis, Roberta, Al-Darmarki, Salma, Flinko, Robin, Lovo, Elena, Wu, Xueji, Robinson, James E., Seaman, Michael S., Fouts, Timothy R., Gallo, Robert C., DeVico, Anthony L., and Lewis, George K. Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding. United States: N. p., 2012. Web. doi:10.1073/pnas.1217609110.
Guan, Yongjun, Pazgier, Marzena, Sajadi, Mohammad M., Kamin-Lewis, Roberta, Al-Darmarki, Salma, Flinko, Robin, Lovo, Elena, Wu, Xueji, Robinson, James E., Seaman, Michael S., Fouts, Timothy R., Gallo, Robert C., DeVico, Anthony L., & Lewis, George K. Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding. United States. doi:10.1073/pnas.1217609110.
Guan, Yongjun, Pazgier, Marzena, Sajadi, Mohammad M., Kamin-Lewis, Roberta, Al-Darmarki, Salma, Flinko, Robin, Lovo, Elena, Wu, Xueji, Robinson, James E., Seaman, Michael S., Fouts, Timothy R., Gallo, Robert C., DeVico, Anthony L., and Lewis, George K. Thu . "Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding". United States. doi:10.1073/pnas.1217609110. https://www.osti.gov/servlets/purl/1136677.
@article{osti_1136677,
title = {Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding},
author = {Guan, Yongjun and Pazgier, Marzena and Sajadi, Mohammad M. and Kamin-Lewis, Roberta and Al-Darmarki, Salma and Flinko, Robin and Lovo, Elena and Wu, Xueji and Robinson, James E. and Seaman, Michael S. and Fouts, Timothy R. and Gallo, Robert C. and DeVico, Anthony L. and Lewis, George K.},
abstractNote = {The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. In conclusion, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.},
doi = {10.1073/pnas.1217609110},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 1,
volume = 110,
place = {United States},
year = {2012},
month = {12}
}

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Works referenced in this record:

Stabilization of the Soluble, Cleaved, Trimeric Form of the Envelope Glycoprotein Complex of Human Immunodeficiency Virus Type 1
journal, September 2002


The CCP4 suite programs for protein crystallography
journal, September 1994


Coot model-building tools for molecular graphics
journal, November 2004

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