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Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

ABSTRACT: Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains.

SUBMITTER: Williams LD

PROVIDER: S-EPMC5905719 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

Williams LaTonya D LD Ofek Gilad G Schätzle Sebastian S McDaniel Jonathan R JR Lu Xiaozhi X Nicely Nathan I NI Wu Liming L Lougheed Caleb S CS Bradley Todd T Louder Mark K MK McKee Krisha K Bailer Robert T RT O'Dell Sijy S Georgiev Ivelin S IS Seaman Michael S MS Parks Robert J RJ Marshall Dawn J DJ Anasti Kara K Yang Guang G Nie Xiaoyan X Tumba Nancy L NL Wiehe Kevin K Wagh Kshitij K Korber Bette B Kepler Thomas B TB Munir Alam S S Morris Lynn L Kamanga Gift G Cohen Myron S MS Bonsignori Mattia M Xia Shi-Mao SM Montefiori David C DC Kelsoe Garnett G Gao Feng F Mascola John R JR Moody M Anthony MA Saunders Kevin O KO Liao Hua-Xin HX Tomaras Georgia D GD Georgiou George G Haynes Barton F BF

Science immunology 20170101 7

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1-specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1-infected individual were used ...[more]

PMID: 28783671

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Project description:The development of HIV broadly neutralizing antibodies (bNAbs) has previously been shown to be associated with viral evolution and high levels of genetic diversity in the HIV envelope (Env) glycoprotein. However, few studies have examined Env evolution in those who fail to develop neutralization breadth in order to assess whether bNAbs result from distinct evolutionary pathways. We compared Env evolution in eight HIV-1-infected participants who developed bNAbs to six donors with similar viral loads who did not develop bNAbs over three years of infection. We focused on Env V1V2 and C3V4, as these are major targets for both strain-specific neutralizing antibodies (nAbs) and bNAbs. Overall evolutionary rates (ranging from 9.92 × 10-3 to 4.1 × 10-2 substitutions/site/year) and viral diversity (from 1.1% to 6.5%) across Env, and within targeted epitopes, did not distinguish bNAb donors from non-bNAb donors. However, bNAb participants had more positively selected residues within epitopes than those without bNAbs, and several of these were common among bNAb donors. A comparison of the kinetics of strain-specific nAbs and bNAbs indicated that selection pressure at these residues increased with the onset of breadth. These data suggest that highly targeted viral evolution rather than overall envelope diversity is associated with neutralization breadth. The association of shared positively selected sites with the onset of breadth highlights the importance of diversity at specific positions in these epitopes for bNAb development, with implications for the development of sequential and cocktail immunization strategies.IMPORTANCE Millions of people are still being infected with HIV decades after the first recognition of the virus. Currently, no vaccine is able to elicit bNAbs that will prevent infection by global HIV strains. Several studies have implicated HIV Env diversity in the development of breadth. However, Env evolution in individuals who fail to develop breadth despite mounting potent strain-specific neutralizing responses has not been well defined. Using longitudinal neutralization, epitope mapping, and sequence data from 14 participants, we found that overall measures of viral diversity were similar in all donors. However, the number of positively selected sites within Env epitopes was higher in bNAb participants than in strain-specific donors. We further identified common sites that were positively selected as bNAbs developed. These data indicate that while viral diversity is required for breadth, this should be highly targeted to specific residues to shape the elicitation of bNAbs by vaccination.

Dataset Information

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

Publications

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

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