Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial
Identifieur interne : 000F83 ( Pmc/Curation ); précédent : 000F82; suivant : 000F84Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial
Auteurs : Paul T. Edlefsen [États-Unis] ; Morgane Rolland [États-Unis] ; Tomer Hertz [États-Unis, Israël] ; Sodsai Tovanabutra [États-Unis] ; Andrew J. Gartland [États-Unis] ; Allan C. Decamp [États-Unis] ; Craig A. Magaret [États-Unis] ; Hasan Ahmed [États-Unis] ; Raphael Gottardo [États-Unis] ; Michal Juraska [États-Unis] ; Connor Mccoy [États-Unis] ; Brendan B. Larsen [États-Unis] ; Eric Sanders-Buell [États-Unis] ; Chris Carrico [États-Unis] ; Sergey Menis [États-Unis] ; Meera Bose [États-Unis] ; Miguel A. Arroyo [Thaïlande] ; Robert J. O Onnell [Thaïlande] ; Sorachai Nitayaphan [Thaïlande] ; Punnee Pitisuttithum [Thaïlande] ; Jaranit Kaewkungwal [Thaïlande] ; Supachai Rerks-Ngarm [Thaïlande] ; Merlin L. Robb [États-Unis] ; Tatsiana Kirys [États-Unis] ; Ivelin S. Georgiev [États-Unis] ; Peter D. Kwong [États-Unis] ; Konrad Scheffler [États-Unis] ; Sergei L. Kosakovsky Pond [États-Unis] ; Jonathan M. Carlson [États-Unis] ; Nelson L. Michael [États-Unis] ; William R. Schief [États-Unis] ; James I. Mullins [États-Unis] ; Jerome H. Kim [États-Unis] ; Peter B. Gilbert [États-Unis]Source :
- PLoS Computational Biology [ 1553-734X ] ; 2015.
Abstract
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.
Url:
DOI: 10.1371/journal.pcbi.1003973
PubMed: 25646817
PubMed Central: 4315437
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<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel</addr-line>
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<country xml:lang="fr">Israël</country>
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<author><name sortKey="Tovanabutra, Sodsai" sort="Tovanabutra, Sodsai" uniqKey="Tovanabutra S" first="Sodsai" last="Tovanabutra">Sodsai Tovanabutra</name>
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<author><name sortKey="Gartland, Andrew J" sort="Gartland, Andrew J" uniqKey="Gartland A" first="Andrew J." last="Gartland">Andrew J. Gartland</name>
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<author><name sortKey="Decamp, Allan C" sort="Decamp, Allan C" uniqKey="Decamp A" first="Allan C." last="Decamp">Allan C. Decamp</name>
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<author><name sortKey="Magaret, Craig A" sort="Magaret, Craig A" uniqKey="Magaret C" first="Craig A." last="Magaret">Craig A. Magaret</name>
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<author><name sortKey="Ahmed, Hasan" sort="Ahmed, Hasan" uniqKey="Ahmed H" first="Hasan" last="Ahmed">Hasan Ahmed</name>
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<author><name sortKey="Gottardo, Raphael" sort="Gottardo, Raphael" uniqKey="Gottardo R" first="Raphael" last="Gottardo">Raphael Gottardo</name>
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<author><name sortKey="Juraska, Michal" sort="Juraska, Michal" uniqKey="Juraska M" first="Michal" last="Juraska">Michal Juraska</name>
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<author><name sortKey="Mccoy, Connor" sort="Mccoy, Connor" uniqKey="Mccoy C" first="Connor" last="Mccoy">Connor Mccoy</name>
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<author><name sortKey="Larsen, Brendan B" sort="Larsen, Brendan B" uniqKey="Larsen B" first="Brendan B." last="Larsen">Brendan B. Larsen</name>
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<author><name sortKey="Sanders Buell, Eric" sort="Sanders Buell, Eric" uniqKey="Sanders Buell E" first="Eric" last="Sanders-Buell">Eric Sanders-Buell</name>
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<author><name sortKey="Menis, Sergey" sort="Menis, Sergey" uniqKey="Menis S" first="Sergey" last="Menis">Sergey Menis</name>
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</nlm:aff>
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<author><name sortKey="Bose, Meera" sort="Bose, Meera" uniqKey="Bose M" first="Meera" last="Bose">Meera Bose</name>
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<author><name sortKey="Arroyo, Miguel A" sort="Arroyo, Miguel A" uniqKey="Arroyo M" first="Miguel A." last="Arroyo">Miguel A. Arroyo</name>
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<author><name sortKey="O Onnell, Robert J" sort="O Onnell, Robert J" uniqKey="O Onnell R" first="Robert J." last="O Onnell">Robert J. O Onnell</name>
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<author><name sortKey="Nitayaphan, Sorachai" sort="Nitayaphan, Sorachai" uniqKey="Nitayaphan S" first="Sorachai" last="Nitayaphan">Sorachai Nitayaphan</name>
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<author><name sortKey="Pitisuttithum, Punnee" sort="Pitisuttithum, Punnee" uniqKey="Pitisuttithum P" first="Punnee" last="Pitisuttithum">Punnee Pitisuttithum</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Faculty of Tropical Medicine, Mahidol University, Bangkok</wicri:regionArea>
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<author><name sortKey="Kaewkungwal, Jaranit" sort="Kaewkungwal, Jaranit" uniqKey="Kaewkungwal J" first="Jaranit" last="Kaewkungwal">Jaranit Kaewkungwal</name>
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</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Royal Thai Army Component, AFRIMS, Bangkok</wicri:regionArea>
</affiliation>
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<author><name sortKey="Rerks Ngarm, Supachai" sort="Rerks Ngarm, Supachai" uniqKey="Rerks Ngarm S" first="Supachai" last="Rerks-Ngarm">Supachai Rerks-Ngarm</name>
<affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>CDC Department, Thai Ministry of Public Health, Nonthaburi</wicri:regionArea>
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<author><name sortKey="Robb, Merlin L" sort="Robb, Merlin L" uniqKey="Robb M" first="Merlin L." last="Robb">Merlin L. Robb</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kirys, Tatsiana" sort="Kirys, Tatsiana" uniqKey="Kirys T" first="Tatsiana" last="Kirys">Tatsiana Kirys</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Georgiev, Ivelin S" sort="Georgiev, Ivelin S" uniqKey="Georgiev I" first="Ivelin S." last="Georgiev">Ivelin S. Georgiev</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kwong, Peter D" sort="Kwong, Peter D" uniqKey="Kwong P" first="Peter D." last="Kwong">Peter D. Kwong</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Scheffler, Konrad" sort="Scheffler, Konrad" uniqKey="Scheffler K" first="Konrad" last="Scheffler">Konrad Scheffler</name>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Department of Medicine, University of California, San Diego, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pond, Sergei L Kosakovsky" sort="Pond, Sergei L Kosakovsky" uniqKey="Pond S" first="Sergei L. Kosakovsky" last="Pond">Sergei L. Kosakovsky Pond</name>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Department of Medicine, University of California, San Diego, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carlson, Jonathan M" sort="Carlson, Jonathan M" uniqKey="Carlson J" first="Jonathan M." last="Carlson">Jonathan M. Carlson</name>
<affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>eSience Research Group, Microsoft Research, Redmond, Washington, United States of America</addr-line>
</nlm:aff>
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<wicri:regionArea>eSience Research Group, Microsoft Research, Redmond, Washington</wicri:regionArea>
</affiliation>
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<author><name sortKey="Michael, Nelson L" sort="Michael, Nelson L" uniqKey="Michael N" first="Nelson L." last="Michael">Nelson L. Michael</name>
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</nlm:aff>
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</affiliation>
</author>
<author><name sortKey="Schief, William R" sort="Schief, William R" uniqKey="Schief W" first="William R." last="Schief">William R. Schief</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Department of Biochemistry, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mullins, James I" sort="Mullins, James I" uniqKey="Mullins J" first="James I." last="Mullins">James I. Mullins</name>
<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kim, Jerome H" sort="Kim, Jerome H" uniqKey="Kim J" first="Jerome H." last="Kim">Jerome H. Kim</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gilbert, Peter B" sort="Gilbert, Peter B" uniqKey="Gilbert P" first="Peter B." last="Gilbert">Peter B. Gilbert</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial</title>
<author><name sortKey="Edlefsen, Paul T" sort="Edlefsen, Paul T" uniqKey="Edlefsen P" first="Paul T." last="Edlefsen">Paul T. Edlefsen</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rolland, Morgane" sort="Rolland, Morgane" uniqKey="Rolland M" first="Morgane" last="Rolland">Morgane Rolland</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hertz, Tomer" sort="Hertz, Tomer" uniqKey="Hertz T" first="Tomer" last="Hertz">Tomer Hertz</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel</addr-line>
</nlm:aff>
<country xml:lang="fr">Israël</country>
<wicri:regionArea>The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tovanabutra, Sodsai" sort="Tovanabutra, Sodsai" uniqKey="Tovanabutra S" first="Sodsai" last="Tovanabutra">Sodsai Tovanabutra</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gartland, Andrew J" sort="Gartland, Andrew J" uniqKey="Gartland A" first="Andrew J." last="Gartland">Andrew J. Gartland</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Decamp, Allan C" sort="Decamp, Allan C" uniqKey="Decamp A" first="Allan C." last="Decamp">Allan C. Decamp</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Magaret, Craig A" sort="Magaret, Craig A" uniqKey="Magaret C" first="Craig A." last="Magaret">Craig A. Magaret</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ahmed, Hasan" sort="Ahmed, Hasan" uniqKey="Ahmed H" first="Hasan" last="Ahmed">Hasan Ahmed</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gottardo, Raphael" sort="Gottardo, Raphael" uniqKey="Gottardo R" first="Raphael" last="Gottardo">Raphael Gottardo</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Juraska, Michal" sort="Juraska, Michal" uniqKey="Juraska M" first="Michal" last="Juraska">Michal Juraska</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mccoy, Connor" sort="Mccoy, Connor" uniqKey="Mccoy C" first="Connor" last="Mccoy">Connor Mccoy</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Larsen, Brendan B" sort="Larsen, Brendan B" uniqKey="Larsen B" first="Brendan B." last="Larsen">Brendan B. Larsen</name>
<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sanders Buell, Eric" sort="Sanders Buell, Eric" uniqKey="Sanders Buell E" first="Eric" last="Sanders-Buell">Eric Sanders-Buell</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carrico, Chris" sort="Carrico, Chris" uniqKey="Carrico C" first="Chris" last="Carrico">Chris Carrico</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Department of Biochemistry, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Menis, Sergey" sort="Menis, Sergey" uniqKey="Menis S" first="Sergey" last="Menis">Sergey Menis</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Department of Biochemistry, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bose, Meera" sort="Bose, Meera" uniqKey="Bose M" first="Meera" last="Bose">Meera Bose</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Arroyo, Miguel A" sort="Arroyo, Miguel A" uniqKey="Arroyo M" first="Miguel A." last="Arroyo">Miguel A. Arroyo</name>
<affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Royal Thai Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Royal Thai Army Component, AFRIMS, Bangkok</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="O Onnell, Robert J" sort="O Onnell, Robert J" uniqKey="O Onnell R" first="Robert J." last="O Onnell">Robert J. O Onnell</name>
<affiliation wicri:level="1"><nlm:aff id="aff008"><addr-line>US Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>US Army Component, AFRIMS, Bangkok</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nitayaphan, Sorachai" sort="Nitayaphan, Sorachai" uniqKey="Nitayaphan S" first="Sorachai" last="Nitayaphan">Sorachai Nitayaphan</name>
<affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Royal Thai Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Royal Thai Army Component, AFRIMS, Bangkok</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pitisuttithum, Punnee" sort="Pitisuttithum, Punnee" uniqKey="Pitisuttithum P" first="Punnee" last="Pitisuttithum">Punnee Pitisuttithum</name>
<affiliation wicri:level="1"><nlm:aff id="aff009"><addr-line>Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Faculty of Tropical Medicine, Mahidol University, Bangkok</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kaewkungwal, Jaranit" sort="Kaewkungwal, Jaranit" uniqKey="Kaewkungwal J" first="Jaranit" last="Kaewkungwal">Jaranit Kaewkungwal</name>
<affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Royal Thai Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Royal Thai Army Component, AFRIMS, Bangkok</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rerks Ngarm, Supachai" sort="Rerks Ngarm, Supachai" uniqKey="Rerks Ngarm S" first="Supachai" last="Rerks-Ngarm">Supachai Rerks-Ngarm</name>
<affiliation wicri:level="1"><nlm:aff id="aff010"><addr-line>CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand</addr-line>
</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>CDC Department, Thai Ministry of Public Health, Nonthaburi</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Robb, Merlin L" sort="Robb, Merlin L" uniqKey="Robb M" first="Merlin L." last="Robb">Merlin L. Robb</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kirys, Tatsiana" sort="Kirys, Tatsiana" uniqKey="Kirys T" first="Tatsiana" last="Kirys">Tatsiana Kirys</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Georgiev, Ivelin S" sort="Georgiev, Ivelin S" uniqKey="Georgiev I" first="Ivelin S." last="Georgiev">Ivelin S. Georgiev</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kwong, Peter D" sort="Kwong, Peter D" uniqKey="Kwong P" first="Peter D." last="Kwong">Peter D. Kwong</name>
<affiliation wicri:level="1"><nlm:aff id="aff011"><addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Scheffler, Konrad" sort="Scheffler, Konrad" uniqKey="Scheffler K" first="Konrad" last="Scheffler">Konrad Scheffler</name>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Department of Medicine, University of California, San Diego, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pond, Sergei L Kosakovsky" sort="Pond, Sergei L Kosakovsky" uniqKey="Pond S" first="Sergei L. Kosakovsky" last="Pond">Sergei L. Kosakovsky Pond</name>
<affiliation wicri:level="1"><nlm:aff id="aff012"><addr-line>Department of Medicine, University of California, San Diego, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carlson, Jonathan M" sort="Carlson, Jonathan M" uniqKey="Carlson J" first="Jonathan M." last="Carlson">Jonathan M. Carlson</name>
<affiliation wicri:level="1"><nlm:aff id="aff013"><addr-line>eSience Research Group, Microsoft Research, Redmond, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>eSience Research Group, Microsoft Research, Redmond, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Michael, Nelson L" sort="Michael, Nelson L" uniqKey="Michael N" first="Nelson L." last="Michael">Nelson L. Michael</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Schief, William R" sort="Schief, William R" uniqKey="Schief W" first="William R." last="Schief">William R. Schief</name>
<affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Department of Biochemistry, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biochemistry, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff014"><addr-line>Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mullins, James I" sort="Mullins, James I" uniqKey="Mullins J" first="James I." last="Mullins">James I. Mullins</name>
<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kim, Jerome H" sort="Kim, Jerome H" uniqKey="Kim J" first="Jerome H." last="Kim">Jerome H. Kim</name>
<affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>US Military HIV Research Program, Silver Spring, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gilbert, Peter B" sort="Gilbert, Peter B" uniqKey="Gilbert P" first="Peter B." last="Gilbert">Peter B. Gilbert</name>
<affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Computational Biology</title>
<idno type="ISSN">1553-734X</idno>
<idno type="eISSN">1553-7358</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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<profileDesc><textClass></textClass>
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<front><div type="abstract" xml:lang="en"><p>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.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rerks Ngarm, S" uniqKey="Rerks Ngarm S">S Rerks-Ngarm</name>
</author>
<author><name sortKey="Pitisuttithum, P" uniqKey="Pitisuttithum P">P Pitisuttithum</name>
</author>
<author><name sortKey="Nitayaphan, S" uniqKey="Nitayaphan S">S Nitayaphan</name>
</author>
<author><name sortKey="Kaewkungwal, J" uniqKey="Kaewkungwal J">J Kaewkungwal</name>
</author>
<author><name sortKey="Chiu, J" uniqKey="Chiu J">J Chiu</name>
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</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pinter, A" uniqKey="Pinter A">A Pinter</name>
</author>
<author><name sortKey="Honnen, Wj" uniqKey="Honnen W">WJ Honnen</name>
</author>
<author><name sortKey="Kayman, Sc" uniqKey="Kayman S">SC Kayman</name>
</author>
<author><name sortKey="Trochev, O" uniqKey="Trochev O">O Trochev</name>
</author>
<author><name sortKey="Wu, Z" uniqKey="Wu Z">Z Wu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Haynes, Bf" uniqKey="Haynes B">BF Haynes</name>
</author>
<author><name sortKey="Gilbert, Pb" uniqKey="Gilbert P">PB Gilbert</name>
</author>
<author><name sortKey="Mcelrath, Mj" uniqKey="Mcelrath M">MJ McElrath</name>
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<author><name sortKey="Zolla Pazner, S" uniqKey="Zolla Pazner S">S Zolla-Pazner</name>
</author>
<author><name sortKey="Tomaras, Gd" uniqKey="Tomaras G">GD Tomaras</name>
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</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yates, Nl" uniqKey="Yates N">NL Yates</name>
</author>
<author><name sortKey="Liao, Hx" uniqKey="Liao H">HX Liao</name>
</author>
<author><name sortKey="Fong, Y" uniqKey="Fong Y">Y Fong</name>
</author>
<author><name sortKey="Decamp, A" uniqKey="Decamp A">A deCamp</name>
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<author><name sortKey="Vandergrift, Na" uniqKey="Vandergrift N">NA Vandergrift</name>
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</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zolla Pazner, S" uniqKey="Zolla Pazner S">S Zolla-Pazner</name>
</author>
<author><name sortKey="Decamp, A" uniqKey="Decamp A">A deCamp</name>
</author>
<author><name sortKey="Gilbert, Pb" uniqKey="Gilbert P">PB Gilbert</name>
</author>
<author><name sortKey="Williams, C" uniqKey="Williams C">C Williams</name>
</author>
<author><name sortKey="Yates, Nl" uniqKey="Yates N">NL Yates</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gottardo, R" uniqKey="Gottardo R">R Gottardo</name>
</author>
<author><name sortKey="Bailer, Rt" uniqKey="Bailer R">RT Bailer</name>
</author>
<author><name sortKey="Korber, Bt" uniqKey="Korber B">BT Korber</name>
</author>
<author><name sortKey="Gnanakaran, S" uniqKey="Gnanakaran S">S Gnanakaran</name>
</author>
<author><name sortKey="Phillips, J" uniqKey="Phillips J">J Phillips</name>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Comput Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Comput. Biol</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">ploscomp</journal-id>
<journal-title-group><journal-title>PLoS Computational Biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-734X</issn>
<issn pub-type="epub">1553-7358</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25646817</article-id>
<article-id pub-id-type="pmc">4315437</article-id>
<article-id pub-id-type="publisher-id">PCOMPBIOL-D-14-01370</article-id>
<article-id pub-id-type="doi">10.1371/journal.pcbi.1003973</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial</article-title>
<alt-title alt-title-type="running-head">Comprehensive Sieve Analysis of RV144</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Edlefsen</surname>
<given-names>Paul T.</given-names>
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<xref ref-type="aff" rid="aff001"><sup>1</sup>
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<xref ref-type="corresp" rid="cor001">*</xref>
<xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup>
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<given-names>Morgane</given-names>
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<xref ref-type="aff" rid="aff002"><sup>2</sup>
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<xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup>
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</contrib>
<contrib contrib-type="author"><name><surname>Hertz</surname>
<given-names>Tomer</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tovanabutra</surname>
<given-names>Sodsai</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="econtrib001"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gartland</surname>
<given-names>Andrew J.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>deCamp</surname>
<given-names>Allan C.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Magaret</surname>
<given-names>Craig A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ahmed</surname>
<given-names>Hasan</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gottardo</surname>
<given-names>Raphael</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Juraska</surname>
<given-names>Michal</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>McCoy</surname>
<given-names>Connor</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Larsen</surname>
<given-names>Brendan B.</given-names>
</name>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sanders-Buell</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Carrico</surname>
<given-names>Chris</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Menis</surname>
<given-names>Sergey</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bose</surname>
<given-names>Meera</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><collab>RV144 Sequencing Team</collab>
<xref ref-type="author-notes" rid="fn001"><sup>¶</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arroyo</surname>
<given-names>Miguel A.</given-names>
</name>
<xref ref-type="aff" rid="aff007"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>O’Connell</surname>
<given-names>Robert J.</given-names>
</name>
<xref ref-type="aff" rid="aff008"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nitayaphan</surname>
<given-names>Sorachai</given-names>
</name>
<xref ref-type="aff" rid="aff007"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pitisuttithum</surname>
<given-names>Punnee</given-names>
</name>
<xref ref-type="aff" rid="aff009"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaewkungwal</surname>
<given-names>Jaranit</given-names>
</name>
<xref ref-type="aff" rid="aff007"><sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rerks-Ngarm</surname>
<given-names>Supachai</given-names>
</name>
<xref ref-type="aff" rid="aff010"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Robb</surname>
<given-names>Merlin L.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kirys</surname>
<given-names>Tatsiana</given-names>
</name>
<xref ref-type="aff" rid="aff011"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Georgiev</surname>
<given-names>Ivelin S.</given-names>
</name>
<xref ref-type="aff" rid="aff011"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kwong</surname>
<given-names>Peter D.</given-names>
</name>
<xref ref-type="aff" rid="aff011"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scheffler</surname>
<given-names>Konrad</given-names>
</name>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pond</surname>
<given-names>Sergei L. Kosakovsky</given-names>
</name>
<xref ref-type="aff" rid="aff012"><sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Carlson</surname>
<given-names>Jonathan M.</given-names>
</name>
<xref ref-type="aff" rid="aff013"><sup>13</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Michael</surname>
<given-names>Nelson L.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schief</surname>
<given-names>William R.</given-names>
</name>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
<xref ref-type="aff" rid="aff014"><sup>14</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mullins</surname>
<given-names>James I.</given-names>
</name>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Jerome H.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gilbert</surname>
<given-names>Peter B.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>US Military HIV Research Program, Silver Spring, Maryland, United States of America</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Department of Biochemistry, University of Washington, Seattle, Washington, United States of America</addr-line>
</aff>
<aff id="aff006"><label>6</label>
<addr-line>IAVI Neutralizing Antibody Center and Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America</addr-line>
</aff>
<aff id="aff007"><label>7</label>
<addr-line>Royal Thai Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</aff>
<aff id="aff008"><label>8</label>
<addr-line>US Army Component, AFRIMS, Bangkok, Thailand</addr-line>
</aff>
<aff id="aff009"><label>9</label>
<addr-line>Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand</addr-line>
</aff>
<aff id="aff010"><label>10</label>
<addr-line>CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand</addr-line>
</aff>
<aff id="aff011"><label>11</label>
<addr-line>Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America</addr-line>
</aff>
<aff id="aff012"><label>12</label>
<addr-line>Department of Medicine, University of California, San Diego, La Jolla, California, United States of America</addr-line>
</aff>
<aff id="aff013"><label>13</label>
<addr-line>eSience Research Group, Microsoft Research, Redmond, Washington, United States of America</addr-line>
</aff>
<aff id="aff014"><label>14</label>
<addr-line>Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Peters</surname>
<given-names>Bjoern</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>La Jolla Institute for Allergy and Immunology, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: MR ST ESB NLM JHK JIM. Performed the experiments: RJO SN PP JK SRN MLR NLM JHK BBL SN MB MAA. Analyzed the data: PTE MR TH PBG BBL SLKP KS WD BSM AJG ACd CAM HA MJ JMC CM RG. Contributed reagents/materials/analysis tools: CC SM WRS JSM ISG TK PDK RG. Wrote the paper: PTE MR TH ST PBG.</p>
</fn>
<fn fn-type="other" id="econtrib001"><p>‡ These authors contributed equally to this work.</p>
</fn>
<fn fn-type="other" id="fn001"><p>¶ Membership of the RV144 Sequencing Team is provided in the Acknowledgments.</p>
</fn>
<corresp id="cor001">* E-mail: <email>pedlefse@fredhutch.org</email>
</corresp>
</author-notes>
<pub-date pub-type="collection"><month>2</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>3</day>
<month>2</month>
<year>2015</year>
</pub-date>
<volume>11</volume>
<issue>2</issue>
<elocation-id>e1003973</elocation-id>
<history><date date-type="received"><day>24</day>
<month>7</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>8</day>
<month>10</month>
<year>2014</year>
</date>
</history>
<permissions><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="pcbi.1003973.pdf"></self-uri>
<abstract><p>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.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>We present an analysis of the genomes of the HIV viruses that infected some participants of the RV144 Thai trial, which was the first study to show efficacy of a vaccine to prevent HIV infection. We analyzed the HIV genomes of infected vaccine recipients and infected placebo recipients, and found differences between them. These differences coincide with previously-studied genetic features that are relevant to the biology of HIV infection, including features involved in immune recognition of the virus. The findings presented here generate testable hypotheses about the mechanism of the partial protection seen in the Thai trial, and may ultimately lead to improved vaccines. The article also presents a toolkit of methods for computational analyses that can be applied to other vaccine efficacy trials.</p>
</abstract>
<funding-group><funding-statement>This study was supported in part by an Interagency Agreement Y1-AI-2642-12 between U.S. Army Medical Research and Material Command (USAMRMC), the National Institutes of Allergy and Infectious Diseases, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and development. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). Additional support was provided by Intramural funding of the Vaccine Research Center, NIAID/NIH and to PBG through the NIH grant 2R37AI05465-11. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Department of Health and Human Services, National Institute for Allergy and Infectious Diseases, the Department of the Army, the Department of Defense, or the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="7"></fig-count>
<table-count count="6"></table-count>
<page-count count="37"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files, except the sequence data. Sequences are available from the GenBank database (accession numbers JX446645–JX448316).</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files, except the sequence data. Sequences are available from the GenBank database (accession numbers JX446645–JX448316).</p>
</notes>
</front>
</pmc>
</record>
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