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Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.

ABSTRACT: Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

SUBMITTER: Wu X

PROVIDER: S-EPMC3516815 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.

Wu Xueling X Zhou Tongqing T Zhu Jiang J Zhang Baoshan B Georgiev Ivelin I Wang Charlene C Chen Xuejun X Longo Nancy S NS Louder Mark M McKee Krisha K O'Dell Sijy S Perfetto Stephen S Schmidt Stephen D SD Shi Wei W Wu Lan L Yang Yongping Y Yang Zhi-Yong ZY Yang Zhongjia Z Zhang Zhenhai Z Bonsignori Mattia M Crump John A JA Kapiga Saidi H SH Sam Noel E NE Haynes Barton F BF Simek Melissa M Burton Dennis R DR Koff Wayne C WC Doria-Rose Nicole A NA Connors Mark M Mullikin James C JC Nabel Gary J GJ Roederer Mario M Shapiro Lawrence L Kwong Peter D PD Mascola John R JR

Science (New York, N.Y.) 20110811 6049

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of a ...[more]

PMID: 21835983

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Project description:Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95%CI: 1.28-3.64, p?=?0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI: 1.49-4.58, p?=?0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.

Dataset Information

Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.

Publications

Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing.

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