Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations.

Amna Malik,Rabiah Fardoos,Philippa C Matthews,Lynn Riddell,Philip J R Goulder,Søren Buus,Fabian Chen,Anne Edwards,Julia Roider,Mai C Severinsen,Henrik Kløverpris,Emily Adland,Pieter Jooste,Leana Laker,Naglaa H Shoukry

doi:10.1371/journal.pone.0189612

Abstract

More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-γ ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.

Highlights

Human cytomegalovirus (CMV) is a ubiquitous beta human herpesvirus
The prevalence of CMV infection is very high in developing countries [1] [2] and is endemic in sub-Saharan African populations with almost two-thirds of infants infected by 3 months of age and 85% infected by a year [3]
We focus here on the CMV-specific CD8+ Tcell response, since firstly, T-cell immunity plays an important role in controlling CMV infection [7] and preventing symptomatic, disseminated CMV disease [8,9,10] and secondly, the frequency of CMV-specific T-cell responses is unusually high, on average 10% of the CD4+ and CD8+ T-cell memory compartments in adult peripheral blood [11]

Summary

Introduction

Human cytomegalovirus (CMV) is a ubiquitous beta human herpesvirus. The prevalence of CMV infection is very high in developing countries [1] [2] and is endemic in sub-Saharan African populations with almost two-thirds of infants infected by 3 months of age and 85% infected by a year [3]. By adolescence CMV infection is virtually universal in sub-Saharan Africa [1]. CMV infection is usually asymptomatic but can lead to severe clinical complications in patients who are immunocompromised [4,5,6]. We focus here on the CMV-specific CD8+ Tcell response, since firstly, T-cell immunity plays an important role in controlling CMV infection [7] and preventing symptomatic, disseminated CMV disease [8,9,10] and secondly, the frequency of CMV-specific T-cell responses is unusually high, on average 10% of the CD4+ and CD8+ T-cell memory compartments in adult peripheral blood [11]. High magnitude CMVspecific T-cell responses have been demonstrated in infancy [12]

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