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Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.
Edlefsen, Paul T; Rolland, Morgane; Hertz, Tomer; Tovanabutra, Sodsai; Gartland, Andrew J; deCamp, Allan C; Magaret, Craig A; Ahmed, Hasan; Gottardo, Raphael; Juraska, Michal; McCoy, Connor; Larsen, Brendan B; Sanders-Buell, Eric; Carrico, Chris; Menis, Sergey; Kijak, Gustavo H; Bose, Meera; Arroyo, Miguel A; O'Connell, Robert J; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Rerks-Ngarm, Supachai; Robb, Merlin L; Kirys, Tatsiana; Georgiev, Ivelin S; Kwong, Peter D; Scheffler, Konrad; Pond, Sergei L Kosakovsky; Carlson, Jonathan M; Michael, Nelson L; Schief, William R; Mullins, James I; Kim, Jerome H; Gilbert, Peter B.
Afiliação
  • Edlefsen PT; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Rolland M; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Hertz T; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion Universit
  • Tovanabutra S; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Gartland AJ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • deCamp AC; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Magaret CA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Ahmed H; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Gottardo R; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Juraska M; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • McCoy C; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • Larsen BB; Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
  • Sanders-Buell E; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Carrico C; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America; IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America.
  • Menis S; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America; IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America.
  • Kijak GH; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Bose M; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Arroyo MA; Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
  • O'Connell RJ; US Army Component, AFRIMS, Bangkok, Thailand.
  • Nitayaphan S; Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
  • Pitisuttithum P; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Kaewkungwal J; Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
  • Rerks-Ngarm S; CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand.
  • Robb ML; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Kirys T; Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
  • Georgiev IS; Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
  • Kwong PD; Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
  • Scheffler K; Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
  • Pond SL; Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
  • Carlson JM; eSience Research Group, Microsoft Research, Redmond, Washington, United States of America.
  • Michael NL; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Schief WR; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America; IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America; Ragon Institute of MGH, MIT and
  • Mullins JI; Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
  • Kim JH; US Military HIV Research Program, Silver Spring, Maryland, United States of America.
  • Gilbert PB; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
PLoS Comput Biol ; 11(2): e1003973, 2015 Feb.
Article em En | MEDLINE | ID: mdl-25646817
The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or "signatures" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por HIV / HIV-1 / Vacinas contra a AIDS / Proteínas do Vírus da Imunodeficiência Humana Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: PLoS Comput Biol Assunto da revista: BIOLOGIA / INFORMATICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções por HIV / HIV-1 / Vacinas contra a AIDS / Proteínas do Vírus da Imunodeficiência Humana Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: PLoS Comput Biol Assunto da revista: BIOLOGIA / INFORMATICA MEDICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos