Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.
Détails
ID Serval
serval:BIB_F93FCA3CDFBF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.
Périodique
PLoS computational biology
Collaborateur⸱rice⸱s
RV144 Sequencing Team
Contributeur⸱rice⸱s
Howell S., Bates A., Lazzaro M., O'Sullivan A., Lei E., Bradfield A., Ibitamuno G., Assawadarachai V., Chen L., Konopa P., Nariya S., Stoddard J.N., Wong K., Zhao H., Deng W., Maust B.S.
ISSN
1553-7358 (Electronic)
ISSN-L
1553-734X
Statut éditorial
Publié
Date de publication
02/2015
Peer-reviewed
Oui
Volume
11
Numéro
2
Pages
e1003973
Langue
anglais
Notes
Publication types: Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: epublish
Publication Status: epublish
Résumé
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.
Mots-clé
AIDS Vaccines/genetics, AIDS Vaccines/immunology, Binding Sites/genetics, Genome, Viral/genetics, HIV Infections/immunology, HIV Infections/prevention & control, HIV Infections/virology, HIV-1/genetics, HIV-1/immunology, Human Immunodeficiency Virus Proteins/chemistry, Human Immunodeficiency Virus Proteins/genetics, Humans, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Sequence Analysis, Protein
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/02/2022 11:45
Dernière modification de la notice
23/03/2024 7:24