title: Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.
abstract: 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.
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Wagh
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.|Santa Fe Institute, Santa Fe, New Mexico, United States of America.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.affiliation: Division of Medical Virology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and NHLS, Cape Town, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Robles
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Bayne
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Jetta
authors.initials: J
authors.lastname: Garrity
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Rist
authors.affiliation: Division of Medical Virology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and NHLS, Cape Town, South Africa.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rademeyer
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Lapedes
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kelli
authors.initials: K
authors.lastname: Greene
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.affiliation: University of KwaZulu-Natal, Durban Department of Immunology and Microbial Science, Durban, South Africa.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Salim Abdool
authors.initials: SA
authors.lastname: Karim
authors.affiliation: The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.|National Institute for Communicable Diseases (NICD), NHLS, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies