Publication:
Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial

Issued Date

2015-01-01

Resource Type

Article

ISSN

15537358
1553734X

DOI

10.1371/journal.pcbi.1003973

Other identifier(s)

2-s2.0-84995610492

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

PLoS Computational Biology. Vol.11, No.2 (2015)

Suggested Citation

Paul T. Edlefsen, Morgane Rolland, Tomer Hertz, Sodsai Tovanabutra, Andrew J. Gartland, Allan C. deCamp, Craig A. Magaret, Hasan Ahmed, Raphael Gottardo, Michal Juraska, Connor McCoy, Brendan B. Larsen, Eric Sanders-Buell, Chris Carrico, Sergey Menis, Meera Bose, Miguel A. Arroyo, Robert J. O’Connell, Sorachai Nitayaphan, Punnee Pitisuttithum, Jaranit Kaewkungwal, Supachai Rerks-Ngarm, Merlin L. Robb, Tatsiana Kirys, Ivelin S. Georgiev, Peter D. Kwong, Konrad Scheffler, Sergei L.Kosakovsky Pond, Jonathan M. Carlson, Nelson L. Michael, William R. Schief, James I. Mullins, Jerome H. Kim, Peter B. Gilbert, Shana Howell, Adam Bates, Michelle Lazzaro, Annemarie O’Sullivan, Esther Lei, Andrea Bradfield, Grace Ibitamuno, Vatcharain Assawadarachai, Lennie Chen, Philip Konopa, Snehal Nariya, Julia N. Stoddard, Kim Wong, Hong Zhao, Wenjie Deng, Brandon S. Maust Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial. PLoS Computational Biology. Vol.11, No.2 (2015). doi:10.1371/journal.pcbi.1003973 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/35298

Research Projects

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Title

Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial

Author(s)

Paul T. Edlefsen
 Morgane Rolland
 Tomer Hertz
 Sodsai Tovanabutra
 Andrew J. Gartland
 Allan C. deCamp
 Craig A. Magaret
 Hasan Ahmed
 Raphael Gottardo
 Michal Juraska
 Connor McCoy
 Brendan B. Larsen
 Eric Sanders-Buell
 Chris Carrico
 Sergey Menis
 Meera Bose
 Miguel A. Arroyo
 Robert J. O’Connell
 Sorachai Nitayaphan
 Punnee Pitisuttithum
 Jaranit Kaewkungwal
 Supachai Rerks-Ngarm
 Merlin L. Robb
 Tatsiana Kirys
 Ivelin S. Georgiev
 Peter D. Kwong
 Konrad Scheffler
 Sergei L.Kosakovsky Pond
 Jonathan M. Carlson
 Nelson L. Michael
 William R. Schief
 James I. Mullins
 Jerome H. Kim
 Peter B. Gilbert
 Shana Howell
 Adam Bates
 Michelle Lazzaro
 Annemarie O’Sullivan
 Esther Lei
 Andrea Bradfield
 Grace Ibitamuno
 Vatcharain Assawadarachai
 Lennie Chen
 Philip Konopa
 Snehal Nariya
 Julia N. Stoddard
 Kim Wong
 Hong Zhao
 Wenjie Deng
 Brandon S. Maust

Other Contributor(s)

Fred Hutchinson Cancer Research Center
 US Military HIV Research Program
 Ben-Gurion University of the Negev
 University of Washington, Seattle
 Scripps Research Institute
 Armed Forces Research Institute of Medical Sciences, Thailand
 Mahidol University
 Thailand Ministry of Public Health
 National Institute of Allergy and Infectious Diseases
 University of California, San Diego
 Microsoft Research
 Massachusetts Institute of Technology

Abstract

© 2015 Ferdinandy et al. 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.

Keyword(s)

Agricultural and Biological Sciences
 Biochemistry, Genetics and Molecular Biology
 Computer Science
 Environmental Science
 Mathematics

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/35298

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Scopus 2011-2015