title: Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.
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.
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Paul T
authors: PT
authors: Edlefsen
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Morgane
authors: M
authors: Rolland
authors: 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 University of the Negev, Beer-Sheva, Israel.
authors: Tomer
authors: T
authors: Hertz
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Sodsai
authors: S
authors: Tovanabutra
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Andrew J
authors: AJ
authors: Gartland
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Allan C
authors: AC
authors: deCamp
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Craig A
authors: CA
authors: Magaret
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Hasan
authors: H
authors: Ahmed
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Raphael
authors: R
authors: Gottardo
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Michal
authors: M
authors: Juraska
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Connor
authors: C
authors: McCoy
authors: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors: Brendan B
authors: BB
authors: Larsen
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Eric
authors: E
authors: Sanders-Buell
authors: 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.
authors: Chris
authors: C
authors: Carrico
authors: 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.
authors: Sergey
authors: S
authors: Menis
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Gustavo H
authors: GH
authors: Kijak
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Meera
authors: M
authors: Bose
authors: Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
authors: Miguel A
authors: MA
authors: Arroyo
authors: US Army Component, AFRIMS, Bangkok, Thailand.
authors: Robert J
authors: RJ
authors: O'Connell
authors: Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
authors: Sorachai
authors: S
authors: Nitayaphan
authors: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors: Punnee
authors: P
authors: Pitisuttithum
authors: Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
authors: Jaranit
authors: J
authors: Kaewkungwal
authors: CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand.
authors: Supachai
authors: S
authors: Rerks-Ngarm
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Merlin L
authors: ML
authors: Robb
authors: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors: Tatsiana
authors: T
authors: Kirys
authors: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors: Ivelin S
authors: IS
authors: Georgiev
authors: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
authors: Peter D
authors: PD
authors: Kwong
authors: Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors: Konrad
authors: K
authors: Scheffler
authors: Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors: Sergei L Kosakovsky
authors: SL
authors: Pond
authors: eSience Research Group, Microsoft Research, Redmond, Washington, United States of America.
authors: Jonathan M
authors: JM
authors: Carlson
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Nelson L
authors: NL
authors: Michael
authors: 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 Harvard, Cambridge, Massachusetts, United States of America.
authors: William R
authors: WR
authors: Schief
authors: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors: James I
authors: JI
authors: Mullins
authors: US Military HIV Research Program, Silver Spring, Maryland, United States of America.
authors: Jerome H
authors: JH
authors: Kim
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Peter B
authors: PB
authors: Gilbert
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
chemical_list: D016915:AIDS Vaccines; D054298:Human Immunodeficiency Virus Proteins
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