The Broad Neutralizing Antibody Responses after HIV-1 Superinfection Are Not Dominated by Antibodies Directed to Epitopes Common in Single Infection

PLoS Pathogens

R. Scott McClelland¹  Keshet Ronen¹  Adam Dingens¹  Bingjie Wang¹  Ivelin S. Georgiev¹  Valerie Cortez²  Mitchell M. Chen²  Julie Overbaugh³ 

[1] Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America;Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington, United States of America;Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: HIV-1;    Point mutation;    Antibodies;    Antibody response;    Microbial mutation;    Cloning;    HIV-2;    Plasma proteins;   

DOI  :  10.1371/journal.ppat.1004973

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY