Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques

Viraj Kulkarni,Antonio Valentin,Christian Brander,Kate E Broderick,Candido Alicea,Rashmi Jalah,George N Pavlakis,Margherita Rosati,Sylvie Le Gall,Barbara K Felber,Morgane Rolland,James I Mullins,Niranjan Y Sardesai,Ashish K Singh,Beatriz Mothe

doi:10.1371/journal.pone.0086254

Abstract

HIV sequence diversity and potential decoy epitopes are hurdles in the development of an effective AIDS vaccine. A DNA vaccine candidate comprising of highly conserved p24gag elements (CE) induced robust immunity in all 10 vaccinated macaques, whereas full-length gag DNA vaccination elicited responses to these conserved elements in only 5 of 11 animals, targeting fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length p55gag increased both magnitude of CE responses and breadth of Gag immunity, demonstrating alteration of the hierarchy of epitope recognition in the presence of pre-existing CE-specific responses. Inclusion of a conserved element immunogen provides a novel and effective strategy to broaden responses against highly diverse pathogens by avoiding decoy epitopes, while focusing responses to critical viral elements for which few escape pathways exist.

Highlights

An ideal HIV vaccine should provide protection against all HIV-1 variants
Vaccination with gag DNA induces poor cellular immune responses to Conserved Elements in macaques We investigated whether vaccination with a plasmid expressing native HIV-1 gag elicited conserved elements (CE)-specific immune responses in 11 macaques, measuring the responses 2 weeks after the last gag DNA vaccination (Table 1)
We demonstrate that vaccination of macaques with p24CE DNA vectors induces strong cellular immune responses targeting conserved epitopes within p24gag

Summary

Introduction

HIV-1 is so variable that it may escape immunity provided by the vaccine candidates evaluated to date, due to intrasubtype or even intrahost diversity To address this problem, approaches to maximize immunological strength and breadth are being explored, including strategies that use consensus, center-of-tree or ancestral sequences, multiple strains or mosaic immunogens, immunogens consisting of known epitopes from the database, and chimeric molecules expressing a selection of the most conserved epitopes from different clades of HIV [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. We expand our mouse immunogenicity study to examine the immunogenicity of p24CE DNA in macaques and demonstrate that the combination of p24CE DNA priming followed by p55gag DNA boost provides a novel strategy to increase the magnitude and breadth of immune responses to Gag, including the induction of strong T-cell responses targeting epitopes within the highly Conserved Elements

Results

Discussion

Findings

Materials and Methods