Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia

Abstract

Preeclampsia (typically characterised by new onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease 1 , 2 . Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction but its role in placentally-related disorders of human pregnancy is unknown 3 . We addressed this using RNA-seq metagenomics 4 – 6 of placental samples from normal and complicated pregnancies. Here we show that human herpes virus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of preeclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 preeclampsia cases and 3,854 controls and found an excess of iciHHV-6 in cases (odds ratio (OR) 2.8, 95% CI: 1.4 to 5.6, P=0.008). We validated this finding, comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (OR=2.5, 95% CI: 1.4 to 4.4, P=0.0013). We conclude that iciHHV-6 results in transcription of viral RNA in the human placenta and predisposes to preeclampsia.

Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia

“…This suggests that heterozygote advantage might be related to special circumstances, such as resistance to infectious diseases as proposed for the MHC locus [65] . Thereby, balancing selection of fetal HLA-G alleles points toward pathogen interactions and the suggested association between viral infections and preeclampsia [ 80 , 81 ].…”

The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres

“…Such individual harbors one or more integrated copy of HHV-6B per cell and are referred to as inherited chromosomally-integrated HHV-6B (iciHHV-6B) subjects [ 3 , 13 ]. Large-scale studies have identified iciHHV-6 as a predisposing factor for angina pectoris as well as pre-eclampsia in pregnant women [ 14 , 15 ]. Viral integration into telomeres has been suggested to be an alternative mechanism to maintain the HHV-6B genome during latency [ 11 ] as reported for the highly oncogenic Marek’s disease virus [ 16 ].…”

Human Herpesviruses 6A and 6B in Reproductive Diseases

“…Quantitation of the viral DNA, and study of the DNA from both parents, confirmed that in 70% of the positive cases the viral genes had been inherited from either the mother or father (iciHHV-6A/B), and that in 30% of cases the virus had been acquired from the mother. Analysis of the inherited DNA sequence and the mRNA sequences found in the placenta confirmed that the inherited viral DNA was transcribing the viral mRNA found in the placenta ( 59 ).…”

“…In the first, the presence of iciHHV-6A/B was determined in cord blood DNA from 368 pregnancies complicated by PE and 3,674 pregnancies without PE. When these subjects were combined with the original cases and controls, iciHHV-6A/B was found in 2.1% of cases vs. 0.8% of controls (OR 2.8, P=0.008) ( 59 ).…”