Human Cytomegalovirus Proteins pp65 and Immediate Early Protein 1 Are Common Targets for CD8+ T Cell Responses in Children with Congenital or Postnatal Human Cytomegalovirus Infection

Abstract

Recombinant modified vaccinia Ankara- and peptide-based IFN-γ ELISPOT assays were used to detect and measure human CMV (HCMV)-specific CD8+ T cell responses to the pp65 (UL83) and immediate early protein 1 (IE1; UL123) gene products in 16 HCMV-infected infants and children. Age at study ranged from birth to 2 years. HCMV-specific CD8+ T cells were detected in 14 (88%) of 16 children at frequencies ranging from 60 to >2000 spots/million PBMC. Responses were detected as early as 1 day of age in infants with documented congenital infection. Nine children responded to both pp65 and IE1, whereas responses to pp65 or IE1 alone were detected in three and two children, respectively. Regardless of the specificity of initial responses, IE1-specific responses predominated by 1 year of age. Changes in HCMV epitopes targeted by the CD8+ T cell responses were observed over time; epitopes commonly recognized by HLA-A2+ adults with latent HCMV infection did not fully account for responses detected in early childhood. Finally, the detection of HCMV-specific CD8+ T cell responses was temporally associated with a decrease in peripheral blood HCMV load. Taken altogether, these data demonstrate that the fetus and young infant can generate virus-specific CD8+ T cell responses. Changes observed in the protein and epitope-specificity of HCMV-specific CD8+ T cells over time are consistent with those observed after other primary viral infections. The temporal association between the detection of HCMV-specific CD8+ T cell responses and the reduction in blood HCMV load supports the importance of CD8+ T cells in controlling primary HCMV viremia.

Interplay between human cytomegalovirus and dendritic cells in T cell activation

“…Within the numerous antigens recognized by memory CD8+ T cells of healthy HCMVseropositive donors tested with various HLA haplotypes, IE1 and pp65 were the most immunodominant, conWrming observations claimed by several groups for many years. Moreover, CTL detected in young infants with HCMV infection were directed at both IE1 and pp65 and their appearance correlated with decrease in viral load [21,22]. This supports the notion that immunodominance could be governed by antigenic dominance, reXecting antigen amounts available at the right time when immunoevasins are not yet eVective.…”

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

“…Thus, it seems that the determination of IE-and pp65-specific CD8 + T cells may in some cases underestimate the real efficiency of the immune system against HCMV infection. In this respect, it seems important to recall that changes in the protein and epitope specificity of HCMVspecific CD8 + T cells over time have been reported in children with congenital or postnatal HCMV infection [18] as well as during Epstein-Barr virus infection [19]. This might be due to different viral antigen processing and presentation [20].…”

Limits and patterns of cytomegalovirus genomic diversity in humans

“…Longitudinal samples were collected from young infants with ages ranging from 1 wk to 2.5 y. Prior reports from our group (63)(64)(65) and others (66) have shown that HCMV-specific CD8 + T-cell responses with similar antigen specificity, phenotype, and functional profiles as adults are detectable in infants with congenital CMV infection, even during gestation. Other studies have shown that infants can generate HIV-specific CD8 + T-cell responses that exert selective pressure and contribute to the evolution of viral quasi-species over the first year of life (67).…”