Abstract
Background: Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth and from which about 20% of infants develop permanent neurodevelopmental effects regardless of presence or absence of symptoms at birth. Viral escape from host immune control may be a mechanism of CMV transmission and infant disease severity. We sought to identify and compare CMV epitopes recognized by mother-infant pairs. We also hypothesized that if immune escape were occurring, then one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition.Methods: The study population consisted of 6 women with primary CMV infection during pregnancy and their infants with cCMV infection. CMV UL83 and UL123 peptides with known or predicted restriction by maternal MHC class I alleles were identified, and a subset was selected for testing based on several criteria. Maternal or infant cells were stimulated with CMV peptides in the IFN-γ ELISpot assay.Results: Overall, 14 of 25 (56%; 8 UL83 and 6 UL123) peptides recognized by mother-infant pairs were not previously reported as CD8 T cell epitopes. Of three pairs with longitudinal samples, one showed maternal loss and infant gain of responses to a CMV epitope restricted by a shared HLA allele.Conclusions: CD8 T cell responses to multiple novel CMV epitopes were identified, particularly in infants. Moreover, the hypothesized pattern of CMV immune escape was observed in one mother-infant pair. These findings emphasize that knowledge of paired CMV epitope recognition allows exploration of viral immune escape that may operate within the maternal-fetal system. Our work provides rationale for future studies of this potential mechanism of CMV transmission during pregnancy or clinical outcomes of infants with cCMV infection.
Highlights
Congenital cytomegalovirus infection is the most common infection acquired before birth, with an incidence of nearly 0.7% of live births in the United States [1]
Predicted to be CMV epitopes based on maternal human leukocyte antigen (HLA) alleles, a total of 28 UL83 or UL123 (IE1) peptides were tested for CD8 T cell responses in 6 mother-infant pairs, of which 25 (89%) elicited detectable responses in the overall cohort (Table 2)
We report results of a pilot study comparing CMV epitopespecific CD8 T cell responses in women with primary CMV infection during pregnancy and their infants with congenital infection
Summary
Congenital cytomegalovirus (cCMV) infection is the most common infection acquired before birth, with an incidence of nearly 0.7% of live births in the United States [1]. CMV-specific CD8 T cells have been detected in fetuses as early as 22–28 weeks gestation [6, 8, 12], and were characterized by oligoclonal expansion and late differentiation phenotype similar to adults [6, 8]. While these responses can increase in frequency and breadth of CMV antigen recognition over time [8], their function may be suboptimal [10, 13]. We hypothesized that if immune escape were occurring, one pattern of longitudinal CD8 T cell responses restricted by shared HLA alleles would be maternal loss (by viral escape) and infant gain (by viral reversion to wildtype) of CMV epitope recognition
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