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

Am J Reprod Immunol. 2019 Oct;82(4):e13174. doi: 10.1111/aji.13174. Epub 2019 Aug 17.


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.

Keywords: HLA-G; NK cells; T cells; idiopathic female infertility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Movement
  • DNA, Viral
  • Endometrium / immunology*
  • Endometrium / virology
  • Epithelial Cells / immunology*
  • Epithelial Cells / virology
  • Female
  • Herpesvirus 6, Human*
  • Humans
  • Infertility / immunology*
  • Infertility / virology
  • Killer Cells, Natural / immunology
  • Roseolovirus Infections / immunology*
  • Roseolovirus Infections / virology
  • Stromal Cells / immunology
  • Stromal Cells / virology
  • T-Lymphocytes / immunology
  • Trophoblasts / physiology*
  • Young Adult


  • DNA, Viral