JVI Accepts, published online ahead of print on 6 August 2008

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J. Virol. doi:10.1128/JVI.00688-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Expansion of HCMV-Immediate Early-1 Specific CD8+ T cells and Control of Human Cytomegalovirus Replication after Allogeneic Stem Cell Transplantation

Karim Sacre, Stéphanie Nguyen, Claire Deback, Guislaine Carcelain, Jean-Paul Vernant, Véronique Leblond, Brigitte Autran^*, and Nathalie Dhedin

Laboratoire d'Immunologie Cellulaire et Tissulaire, INSERM U543, AP-HP, Université Pierre et Marie Curie-Paris6, Paris, France; Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie-Paris6, Paris, France; Laboratoire de Virologie, EA 2387, Université Pierre et Marie Curie-Paris6, Paris, France

^* To whom correspondence should be addressed. Email: brigitte.autran{at}psl.aphp-paris.fr.

Recovery of human cytomegalovirus (HCMV)-specific T immunity is critical for protection against HCMV disease in the early phase after allogeneic stem cell transplantation (SCT). Using an ELISpot assay with overlapping 15-mer peptides spanning pp65 and Immediate Early-1 HCMV proteins, we investigated which HCMV-specific CD8+IFN+ T cell responses against pp65 and IE-1 were associated with control of HCMV replication in 48 recipients of un-manipulated HLA-matched allografts at 3 and 6 months after SCT and in 23 donors. At 3 months after SCT, the magnitude of the pp65-specific IFN- producing CD8+ T cell response was greater in recipients than donors, regardless of HCMV status. In contrast expansion of IE-1-specific CD8 T cells at M3 was associated with protection against HCMV and no patient with this expansion had HCMV replication at M3. At M6, the number of HCMV-specific CD8+ T cells against both pp65 and IE-1 had expanded in all recipients, regardless of their previous level of HCMV replication. The recipients HCMV-specific CD8+ T cells already detectable in related-donors were predominantly targeting pp65. In contrast, in 40% of cases, the HCMV-specific CD8+ T cells in recipients involved new CD8+ T cell specificities undetectable in their related donors and preferentially targeting IE-1. Taken together, these results show that the delay in reconstituting IE-1-specific CD8+ T cells is correlated with the lack of protection against HCMV in the first 3 months after SCT. They also show that IE-1 is a major antigenic determinant of the early restoration of a protective immunity to HCMV after SCT.