Abstract
BackgroundFine definition of targeted CD8+ T-cell epitopes and their human leucocyte antigen (HLA) class I restriction informs iterative improvements of HIV-1 T-cell vaccine designs and may predict early vaccine success or failure. Here, lymphocytes from volunteers, who had received candidate HIVconsv vaccines expressing conserved sub-protein regions of HIV-1, were used to define the optimum-length target epitopes and their HLA restriction. In HIV-1-positive patients, CD8+ T-cell responses predominantly recognize immunodominant, but hypervariable and therefore less protective epitopes. The less variable, more protective epitopes in conserved regions are typically subdominant. Therefore, induction of strong responses to conserved regions by vaccination provides an opportunity to discover novel important epitopes.MethodsCryopreserved lymphocytes from vaccine recipients were expanded by stimulation with 15-mer responder peptides for 10 days to establish short term-cell-line (STCL) effector cells. These were subjected to intracellular cytokine staining using serially truncated peptides and peptide-pulsed 721.221 cells expressing individual HLA class I alleles to define minimal epitope length and HLA restriction by stimulation of IFN-γ and TNF-α production and surface expression of CD107a.ResultsUsing lymphocyte samples of 12 vaccine recipients, we defined 14 previously unreported optimal CD8+ T-cell HIV-1 epitopes and their four-digit HLA allele restriction (6 HLA-A, 7 HLA-B and 1 HLA-C alleles). Further 13 novel targets with incomplete information were revealed.ConclusionsThe high rate of discovery of novel CD8+ T-cell effector epitopes warrants further epitope mining in recipients of the conserved-region vaccines in other populations and informs development of HIV-1/AIDS vaccines.Trial registrationClinicalTrials.gov NCT01151319
Highlights
The protective role of CD8+ T cells against HIV-1 infection has been implicated by combined data from genome-wide association studies, viral sequence polymorphisms and replicative fitness analyses, and longitudinal maps of epitope escape [1,2,3]
For this reason since 1998, the Los Alamos National Laboratory HIV Sequence Database (LANL-HSD; www.hiv.lanl.gov) has been collecting and posting well over 300 of the best-defined, finemapped epitopes in the HIV-1 proteome restricted by over 80 human leucocyte antigen (HLA) class I alleles as the ‘A list’ of HIV-1 CD8+ T-cell epitopes, while the less defined specific T-cell targets are gathered as the ‘B list’ [4]
Molecular typing for HLA-A, HLA-B, HLA-C & HLA-DRB was performed by The DNA Sequencing MISEQ HLA Laboratory, Weatherall Institute of Molecular Medicine, The John Radcliffe, on EDTA blood samples taken from all volunteers prior to vaccination
Summary
The protective role of CD8+ T cells against HIV-1 infection has been implicated by combined data from genome-wide association studies, viral sequence polymorphisms and replicative fitness analyses, and longitudinal maps of epitope escape [1,2,3]. Evidence is emerging that the CD8+ T-cell specificity, cognitive breadth and human lymphocyte antigen (HLA) restriction are crucial determinants of the T-cell response protective efficacy [1,2,3] It follows that careful definition of optimal epitopes can critically inform T-cell vaccine design and increase the power of early prediction of vaccine success or failure. This is because over the course of natural infection, immune responses through the actions of antibodies, CTL and perhaps innate responses drive rapid HIV-1 evolution known as immune escape [7,8,9] Under this strong selective pressure, HIV-1 evolved to have immunodominant epitopes in the most variable regions of its proteins as decoys, while the more functionally/structurally conserved, harder-to-change and more protective determinants remain subdominant [10, 11]. Induction of strong responses to conserved regions by vaccination provides an opportunity to discover novel important epitopes
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