Format

Send to

Choose Destination
PLoS Comput Biol. 2015 Feb 3;11(2):e1003973. doi: 10.1371/journal.pcbi.1003973. eCollection 2015 Feb.

Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.

Author information

1
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
2
US Military HIV Research Program, Silver Spring, Maryland, United States of America.
3
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.
4
Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
5
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.
6
Royal Thai Army Component, AFRIMS, Bangkok, Thailand.
7
US Army Component, AFRIMS, Bangkok, Thailand.
8
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
9
CDC Department, Thai Ministry of Public Health, Nonthaburi, Thailand.
10
Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
11
Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
12
eSience Research Group, Microsoft Research, Redmond, Washington, United States of America.
13
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.

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.

PMID:
25646817
PMCID:
PMC4315437
DOI:
10.1371/journal.pcbi.1003973
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center