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Preeclampsia is a major cause of maternal and perinatal morbidity, but its underlying mechanisms are not fully understood. The objective of this thesis was to investigate whether viral infection, specifically Human herpesvirus-6A/B (HHV-6A/B), may contribute to the development of preeclampsia, using a combination of population-based epidemiology and experimental studies in primary human trophoblast cells.

In paper I, with a Swedish register-based cohort of 618,814 primiparous women we showed that antiviral medication prescription during pregnancy was associated with a lower likelihood of preeclampsia (3.8% vs. 4.4%), an association that remained after adjustment (aOR 0.88; 95% CI 0.81–0.96). The reduction was most pronounced when antiviral therapy was initiated in the third trimester, supporting the hypothesis that viral reactivation may influence preeclampsia risk.

In paper II, we demonstrated that HHV-6A and HHV-6B can infect primary trophoblast cells and induce distinct DNA methylation changes. HHV-6A infection resulted in 37 differentially methylated regions linked to genes involved in angiogenesis and placental development, whereas HHV-6B affected a single but biologically important region in PEG10, a gene important for placental development. These findings provide the first evidence of targeted epigenetic effects of HHV-6A/B in trophoblasts.

In paper III, transcriptomic profiling revealed substantial changes in bulk RNA and miRNA expression following infection, including activation of interferon-mediated antiviral pathways and downregulation of genes involved in angiogenesis and placental function. These results suggest that HHV-6A/B may impair placental development through combined epigenetic and transcriptional mechanisms.

In paper IV, functional analyses showed that both viral variants increased secretion of anti-angiogenic factors such as Soluble fms-like tyrosine kinase-1 and Angiopoietin-2, while HHV-6B induced broader anti-angiogenic shifts, with a reduction in Placental growth factors and increased Vasohibin-1 and Thrombospondin-1. HHV-6A selectively activated the PERK-mediated endoplasmic reticulum stress pathway. Together, these findings show that HHV-6A/B differentially affect trophoblast function at the protein level.

In summary, this thesis supports a broader role for viral infection in preeclampsia and identifies mechanisms by which HHV-6A/B may contribute to disease. We show that HHV-6A/B can infect primary trophoblasts, alter epigenetic and transcriptomic profiles, and disrupt angiogenic and stress-response pathways, offering new insight into viral and molecular drivers of preeclampsia and related pregnancy complications.