Human cytomegalovirus gene products US3 and US6 down-regulate trophoblast class I MHC molecules

The epidemiological correlation between human CMV (HCMV) infection and spon taneous fetal loss has been suggested, but the underlying mechanism is not well understood. Fetal cytotrophoblasts, which are in direct contact with t he maternal immune system in the uterus during pregnancy, do not express HL A-A and HLA-B, but express the nonclassical class I HLA-G and HLA-C, It has been shown that both HLA-G and HLA-C are capable of inhibiting NK-mediated cell lysis, In our present study, using human trophoblast cell lines as we ll as other cell lines stably transfected with the human class I genes, we have demonstrated that HCMV US3 and US6 down-regulate the cell-surface expr ession of both HLA-G and HLA-C by two different mechanisms. HCMV US3 physic ally associates with both trophoblast class I MHC species, retaining them i n the endoplasmic reticulum, In contrast, HCMV US6 inhibits peptide transpo rt by TAP and thus specifically the intracellular trafficking of class I mo lecules. Therefore, these findings suggest for the first time a possible mo lecular mechanism underlying HCMV-related spontaneous pregnancy loss.