By: 20 July 2016
HHV-6A infection of the uterus linked to infertility

A new study reported that HHV-6A infects the lining of the uterus in 43 per cent of women with unexplained infertility but cannot be found in the uterine lining of fertile women.  Furthermore, the cytokine and the natural killer cell profiles were very different in patients with the infection. HHV-6A was found only in uterine endothelial cells, and not in the blood.

A team led by Roberta Rizzo, Roberto Marci, and Dario DiLuca of the University of Ferrara tested endometrial biopsies from 30 women with unexplained primary infertility as well as 36 fertile women. HHV-6 DNA was found in the endometrial samples from 13 of 30 infertile women (43 per cent), but none of the fertile women. Surprisingly, all of the virus was HHV-6A, not HHV-6B,  the virus that reactivates in immunocompromised patients and causes roseola in infants. Over 97 per cent of HHV-6 reactivation in transplant patients is typed as HHV-6B.

Of interest, the investigators found a strong correlation between the level of estradiol and presence of an HHV-6A infection (p=0.02). They also found that the virus was active only during the secretory phase of the menstrual cycle, when estradiol levels were highest. Estradiol has also been shown to cause HSV1 reactivation (Miguel 2010), and steroids cause HHV-6 to reactivate disproportionately in patients with DIHS/DRESS (Ishida 2014).

Cytokine and natural killer (NK) cell levels were significantly different between women who were HHV-6A positive compared to controls and infertile women who were HHV-6A negative. While the Th2 cytokine IL-10 was higher in the HHV-6A positive group, the Th1 cytokine IFN-gamma was lower than in controls or HHV-6A negative women, causing an increase in the Th1/TH2 ratio, a condition common in female infertility. The authors note that HHV-6 is known to increase IL-10 expression by monocytes and reduce IFN-gamma by T lymphocytes.

In addition, levels of a specific subset of uterine NK cells were significantly lower in HHV-6A+ individuals than in the controls, and uterine NK cells from the HHV-6A infected group showed higher activation in response to the virus than the cells collected from controls. The authors suggest that these findings are consistent with an abnormal, persistent immune response toward HHV-6A antigens in this subgroup of women with unexplained infertility.

The HHV-6A DNA was found only in the endometrial epithelial cells, and not the uterine stromal cells. No HHV-6A was found in the peripheral blood, and latent HHV-6B was found in equal amounts in the blood of both patients and controls. As a result, the condition can be diagnosed only by testing a uterine biopsy.

A Japanese study showed that HHV-6 IgG and IgM titers were significantly higher in patients with spontaneous abortions at 6-12 weeks compared to controls, and 8% were IgM positive. HHV-6 antigens were in the villous tissues (Ando 1992). Several other studies have also found HHV-6 DNA in fetal tissue after miscarriage (Drago 2008, Drago 2014, , Revest 2011). Past studies have also found altered cytokine levels in the uterine tissue of infertile women (Ozkan 2014).


Source: HHV-6 Foundation

Reference: Roberto Marci, Valentina Gentili, Daria Bortolotti, Giuseppe Lo Monte, Elisabetta Caselli, Silvia Bolzani, Antonella Rotola, Dario Di Luca, Roberta Rizzo. Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility. PLOS ONE, 2016; 11 (7): e0158304 DOI: 10.1371/journal.pone.0158304