Abstract
To elucidate the roles of human herpesvirus (HHV)-6 primary unexplained infertile women, a prospective randomized study was conducted on a cohort of primary unexplained infertile women and a cohort of control women, with at least one successful pregnancy. HHV-6 DNA was analyzed and the percentage and immune-phenotype of resident endometrial Natural Killer (NK) cells, as the first line of defense towards viral infections, was evaluated in endometrial biopsies. Cytokine levels in uterine flushing samples were analyzed. HHV-6A DNA was found in 43% of endometrial biopsies from primary unexplained infertile women, but not in control women. On the contrary, HHV-6B DNA was absent in endometrial biopsies, but present in PBMCs of both cohorts. Endometrial NK cells presented a different distribution in infertile women with HHV6-A infection compared with infertile women without HHV6-A infection. Notably, we observed a lower percentage of endometrial specific CD56brightCD16- NK cells. We observed an enhanced HHV-6A-specific endometrial NK cell response in HHV-6A positive infertile women, with a marked increase in the number of endometrial NK cells activating towards HHV-6A infected cells. The analysis of uterine flushing samples showed an increase in IL-10 levels and a decrease of IFN-gamma concentrations in infertile women with HHV6-A infection. Our study indicates, for the first time, that HHV-6A infection might be an important factor in female unexplained infertility development, with a possible role in modifying endometrial NK cells immune profile and ability to sustain a successful pregnancy.
Highlights
human herpesvirus (HHV)-6 is an ubiquitous virus that was first discovered in 1986 [1]
: HHV-6 DNA has been detected in genital tract secretions from pregnant and non-pregnant women [17,18,19]; several studies have reported low-level HHV-6 shedding from the genital tract in up to 25% of women [18,19,20,21], with pregnant women characterized by the highest prevalence of shedding [19]; HHV-6 DNA sequences and antigens have been detected in biopsies in archived cervical samples [22,23,24,25,26]
These results are in agreement with literature data [32], that reported the presence of the HHV-6B variant in a 25–30% of peripheral blood samples
Summary
HHV-6 is an ubiquitous virus that was first discovered in 1986 [1]. It has been identified as the etiological agent of roseola infantum, and has been implicated (with various degrees) in a number of conditions such as liver disease [2], pneumonitis [3], myocarditis [4], multiple sclerosis [5], drug induced hypersensitivity syndrome [6, 7], the nodular sclerosis subset of Hodgkin’sPLOS ONE | DOI:10.1371/journal.pone.0158304 July 1, 2016HHV-6A and Female Unexplained Infertility lymphoma [8], and autoimmune diseases [9]. HHV-6 is an ubiquitous virus that was first discovered in 1986 [1]. HHV-6 variants have been recognized as different viral species, on the basis of specific biological, immunological, pathological and molecular characteristics [11]. Both HHV-6 variants infect mainly T-cells it has wide tropism are important differences in cell tropism between HHV-6A and HHV-6B, HHV-6A but not HHV-6B reproduces in human neural stem cells [12], oligodendrocyte progenitor cells [13] and hepatocytes [14] while HHV-6B infection in astrocytes and hepatocytes result in abortive infection. The in-vitro HHV6A infection of cervical carcinoma cell lines [27, 28] raises the possibility that the detection HHV-6 footprints reflect the ability of the virus to infect cervical cells, instead of being attributed to infected lymphocytes present in the tissue
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