Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial
Genre
Journal ArticleDate
2015-01-01Author
Edlefsen, PTRolland, M
Hertz, T
Tovanabutra, S
Gartland, AJ
deCamp, AC
Magaret, CA
Ahmed, H
Gottardo, R
Juraska, M
McCoy, C
Larsen, BB
Sanders-Buell, E
Carrico, C
Menis, S
Bose, M
Arroyo, MA
O’Connell, RJ
Nitayaphan, S
Pitisuttithum, P
Kaewkungwal, J
Rerks-Ngarm, S
Robb, ML
Kirys, T
Georgiev, IS
Kwong, PD
Scheffler, K
Pond, SLK
Carlson, JM
Michael, NL
Schief, WR
Mullins, JI
Kim, JH
Gilbert, PB
Howell, S
Bates, A
Lazzaro, M
O’Sullivan, A
Lei, E
Bradfield, A
Ibitamuno, G
Assawadarachai, V
Chen, L
Konopa, P
Nariya, S
Stoddard, JN
Wong, K
Zhao, H
Deng, W
Maust, BS
Subject
AIDS VaccinesBinding Sites
Genome, Viral
HIV Infections
HIV-1
Human Immunodeficiency Virus Proteins
Humans
Models, Molecular
Molecular Sequence Data
Sequence Alignment
Sequence Analysis, Protein
Permanent link to this record
http://hdl.handle.net/20.500.12613/5269
Metadata
Show full item recordDOI
10.1371/journal.pcbi.1003973Abstract
© 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.Citation to related work
Public Library of Science (PLoS)Has part
PLoS Computational BiologyADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.eduae974a485f413a2113503eed53cd6c53
http://dx.doi.org/10.34944/dspace/5251
Scopus Count
Collections
Except where otherwise noted, this item's license is described as https://creativecommons.org/publicdomain/zero/1.0/