HHV‐6A infection of endometrial epithelial cells affects immune profile and trophoblast invasion.

Problem: We first reported human herpesvirus (HHV)‐6A DNA presence in 43% of endometrial cells from women with idiopathic infertility, whereas no fertile control women harbored the virus. We investigated the effect of HHV‐6A infection on the immunological status of the endometrium. Method of study: Endometrial biopsies, uterine flushing, and whole blood samples were collected from 67 idiopathic infertile women (mid‐secretory phase). We analyzed the endometrial immunological status evaluating: (a) the effect of HHV‐6A infection on endometrial immune profile analyzing the ratio of interleukin (IL)‐15/ fibroblast growth factor‐inducible 14 (Fn‐14) and IL‐18/ TNF‐related weak inducer of apoptosis (TWEAK) mRNA as a biomarker of endometrial (e)natural killer activation/maturation, angiogenesis, and Th1/Th2 balance; (b) endometrial receptivity to trophoblasts in endometrial 3D in vitro model; (c) natural killer (NK) cells and T cells percentage and subpopulations by flow cytometry. Results: We confirmed the presence of HHV‐6A infection in a 40% of idiopathic infertile women, characterized by an immune profile reflecting eNK cell cytotoxic activation and a decrease in CD4+ CD25+ CD127dim/− regulatory T cells. The co‐culture of endometrial epithelial cells with spheroids generated from the extravillous trophoblast‐derived cell line JEG3 showed a twofold expansion of spheroids on endometrial epithelial‐stromal cells (ESC) culture surface from HHV‐6A negative women while no expansion was observed on the surface of ESC from HHV‐6A positive women. Conclusion: The identification of an effect of HHV‐6A infection on endometrial immune status opens new perspectives in idiopathic infertile women care management. In addition, it would be possible to select antiviral therapies as novel, non‐hormonal therapeutic approaches to those idiopathic infertile women characterized by the presence of endometrial HHV‐6A infection, to increase their pregnancy rate. [ABSTRACT FROM AUTHOR]