title: The Broad Neutralizing Antibody Responses after HIV-1 Superinfection Are Not Dominated by Antibodies Directed to Epitopes Common in Single Infection.
abstract: HIV-1 vaccines designed to date have failed to elicit neutralizing antibodies (Nabs) that are capable of protecting against globally diverse HIV-1 subtypes. One relevant setting to study the development of a strong, cross-reactive Nab response is HIV-1 superinfection (SI), defined as sequential infections from different source partners. SI has previously been shown to lead to a broader and more potent Nab response when compared to single infection, but it is unclear whether SI also impacts epitope specificity and if the epitopes targeted after SI differ from those targeted after single infection. Here the post-SI Nab responses were examined from 21 Kenyan women collectively exposed to subtypes A, C, and D and superinfected after a median time of ~1.07 years following initial infection. Plasma samples chosen for analysis were collected at a median time point ~2.72 years post-SI. Because previous studies of singly infected populations with broad and potent Nab responses have shown that the majority of their neutralizing activity can be mapped to 4 main epitopes on the HIV-1 Envelope, we focused on these targets, which include the CD4-binding site, a V1/V2 glycan, the N332 supersite in V3, and the membrane proximal external region of gp41. Using standard epitope mapping techniques that were applied to the previous cohorts, the present study demonstrates that SI did not induce a dominant Nab response to any one of these epitopes in the 21 women. Computational sera delineation analyses also suggested that 20 of the 21 superinfected women's Nab responses could not be ascribed a single specificity with high confidence. These data are consistent with a model in which SI with diverse subtypes promotes the development of a broad polyclonal Nab response, and thus would provide support for vaccine designs using multivalent HIV immunogens to elicit a diverse repertoire of Nabs.
authors.affiliation: Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington, United States of America; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cortez
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Wang
authors.affiliation: Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington, United States of America; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Dingens
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Mitchell M
authors.initials: MM
authors.lastname: Chen
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Keshet
authors.initials: K
authors.lastname: Ronen
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: R Scott
authors.initials: RS
authors.lastname: McClelland
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Overbaugh
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000918:Antibody Specificity; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009500:Neutralization Tests; D015163:Superinfection / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies