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Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

ABSTRACT: Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.

SUBMITTER: Huang J

PROVIDER: S-EPMC5770152 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

Huang Jinghe J Kang Byong H BH Ishida Elise E Zhou Tongqing T Griesman Trevor T Sheng Zizhang Z Wu Fan F Doria-Rose Nicole A NA Zhang Baoshan B McKee Krisha K O'Dell Sijy S Chuang Gwo-Yu GY Druz Aliaksandr A Georgiev Ivelin S IS Schramm Chaim A CA Zheng Anqi A Joyce M Gordon MG Asokan Mangaiarkarasi M Ransier Amy A Darko Sam S Migueles Stephen A SA Bailer Robert T RT Louder Mark K MK Alam S Munir SM Parks Robert R Kelsoe Garnett G Von Holle Tarra T Haynes Barton F BF Douek Daniel C DC Hirsch Vanessa V Seaman Michael S MS Shapiro Lawrence L Mascola John R JR Kwong Peter D PD Connors Mark M

Immunity 20161101 5

Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impac ...[more]

PMID: 27851912

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Project description:UnlabelledAntigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.ImportanceOne of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

Dataset Information

Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

Publications

Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth.

Similar Datasets

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