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Title: Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection

Abstract

In this study, the identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triplemore » and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.« less

Authors:
 [1];  [2];  [3];  [4];  [4];  [4];  [4];  [3];  [1];  [1];  [5];  [5];  [6];  [6];  [7];  [8];  [4];  [9];  [6];  [10] more »;  [5];  [1];  [4] « less
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Santa Fe Institute, Santa Fe, NM (United States)
  3. Univ. of Cape Town and NHLS, Cape Town (South Africa)
  4. Beth Israel Deaconess Medical Center, Boston, MA (United States)
  5. Duke Univ. Medical Center, Durham, NC (United States)
  6. NIAID, NIH, Bethesda, MD (United States)
  7. Univ. of KwaZulu-Natal, Durban (South Africa)
  8. The Scripps Research Institute, La Jolla, CA (United States)
  9. The Rockefeller Univ., New York, NY (United States)
  10. Univ. of KwaZulu-Natal, Durban (South Africa); Univ. of the Witwatersrand, Johannesburg (South Africa)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1291229
Report Number(s):
LA-UR-16-20914
Journal ID: ISSN 1553-7374
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 12; Journal Issue: 3; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biological science; HIV-1; antibodies; antiretrovirals; complement system; immunotherapy; blood plasma; microbial genetics; pharmacokinetics

Citation Formats

Wagh, Kshitij, Bhattacharya, Tanmoy, Williamson, Carolyn, Robles, Alex, Bayne, Madeleine, Garrity, Jetta, Rist, Michael, Rademeyer, Cecilia, Yoon, Hyejin, Lapedes, Alan Scott, Gao, Hongmei, Greene, Kelli, Louder, Mark K., Kong, Rui, Karim, Salim Abdool, Burton, Dennis R., Barouch, Dan H., Nussenzweig, Michael C., Mascola, John R., Morris, Lynn, Montefiori, David, Korber, Bette Tina, and Seamon, Michael S. Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection. United States: N. p., 2016. Web. doi:10.1371/journal.ppat.1005520.
Wagh, Kshitij, Bhattacharya, Tanmoy, Williamson, Carolyn, Robles, Alex, Bayne, Madeleine, Garrity, Jetta, Rist, Michael, Rademeyer, Cecilia, Yoon, Hyejin, Lapedes, Alan Scott, Gao, Hongmei, Greene, Kelli, Louder, Mark K., Kong, Rui, Karim, Salim Abdool, Burton, Dennis R., Barouch, Dan H., Nussenzweig, Michael C., Mascola, John R., Morris, Lynn, Montefiori, David, Korber, Bette Tina, & Seamon, Michael S. Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection. United States. doi:10.1371/journal.ppat.1005520.
Wagh, Kshitij, Bhattacharya, Tanmoy, Williamson, Carolyn, Robles, Alex, Bayne, Madeleine, Garrity, Jetta, Rist, Michael, Rademeyer, Cecilia, Yoon, Hyejin, Lapedes, Alan Scott, Gao, Hongmei, Greene, Kelli, Louder, Mark K., Kong, Rui, Karim, Salim Abdool, Burton, Dennis R., Barouch, Dan H., Nussenzweig, Michael C., Mascola, John R., Morris, Lynn, Montefiori, David, Korber, Bette Tina, and Seamon, Michael S. Wed . "Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection". United States. doi:10.1371/journal.ppat.1005520. https://www.osti.gov/servlets/purl/1291229.
@article{osti_1291229,
title = {Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection},
author = {Wagh, Kshitij and Bhattacharya, Tanmoy and Williamson, Carolyn and Robles, Alex and Bayne, Madeleine and Garrity, Jetta and Rist, Michael and Rademeyer, Cecilia and Yoon, Hyejin and Lapedes, Alan Scott and Gao, Hongmei and Greene, Kelli and Louder, Mark K. and Kong, Rui and Karim, Salim Abdool and Burton, Dennis R. and Barouch, Dan H. and Nussenzweig, Michael C. and Mascola, John R. and Morris, Lynn and Montefiori, David and Korber, Bette Tina and Seamon, Michael S.},
abstractNote = {In this study, the identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.},
doi = {10.1371/journal.ppat.1005520},
journal = {PLoS Pathogens},
number = 3,
volume = 12,
place = {United States},
year = {2016},
month = {3}
}

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