A herpesvirus associated with female infertility

HHV-6Viruses that replicate in the male or female reproductive tract are considered to be potential causes of human infertility. Several herpesviruses have been implicated in male infertility, and now human herpesvirus 6A (HHV-6A) has been found in endometrial cells of women with unexplained infertility (paper link).

HHV-6 was only recently discovered (1986) and is now known to occur as two variants, HHV-6A and HHV-6B. The latter is a major cause of exanthem subitum, a rash of infants, but no disease has been clearly associated with HHV-6A. These viruses are transmitted to infants early in life via saliva, from mother to child, from siblings, or from other infants at day care centers. Seroprevalence studies indicate that almost all children are infected with these viruses by 2 years of age.

To determine if HHV-6 might be a cause of infertility, a study (paper link) was conducted of 30 women with unexplained primary fertility, and 36 women with at least one previous pregnancy. HHV-6B DNA was detected in PBMC from both infertile and fertile groups (25 and 28%, respectively); HHV-6A DNA was not detected. In contrast, endometrial epithelial cells from 13/30 (43%) infertile women were positive for HHV-6A DNA; this viral DNA was not detected in endometrium of fertile women. When placed in culture, endometrial epithelial cells produced viral early and late proteins, suggesting the presence of infectious virus.

Presence of HHV-6A DNA in endometrial epithelial cells was also associated with an altered hormonal and immune environment. Estradiol levels were higher in infected versus uninfected infertile women. The authors suggest that higher levels of this hormone could be involved in allowing HHV-6A infection of the endometrium.

Levels of a specific type of uterine NK cell were lower in HHV-6A positive women, and IL-10 (a Th2 cytokine) was elevated while IFN-gamma (a Th1 cytokine) was decreased. There were no differences in the levels of these cells and cytokines in peripheral blood. These changes are consistent with an increase in the ratio of Th1/Th2 responses that has been documented in female infertility.

The authors also observed enhanced endometrial NK cell responses to HHV-6A in infected but not uninfected women, together with an increase in the number of these cells that are activated when cultured with HHV-6A infected cells.

I wonder what was the source of HHV-6A in the endometrium, as the virus was not detected in blood. Was the infection recently acquired, or did it occur years before, with the virus establishing a chronic infection in the uterus?

The results suggest that HHV-6A infection of the endometrium triggers an abnormal NK cell and cytokine profile, which in turn leads to a uterine environment that is not compatible with fertility. The results need to be confirmed with studies of additional fertile and infertile women. It would also be useful to have an animal model of HHV-6A infection of the endometrium, which could lead to mechanistic work to determine how virus infection causes infertility.

Image: Electron micrograph of HHV-6 (image credit)

TWiV 398: Permission to be intuitive

Vincent speaks with Sandy Weller about her career and her work on the mechanisms of synthesis, maturation, cleavage and packaging of viral DNA genomes.

You can find TWiV 398 at microbe.tv/twiv, or listen/watch below.

Click arrow to play
Download TWiV 398 (36 MB .mp3, 49 min)
Subscribe (free): iTunesRSSemailGoogle Play Music

Become a patron of TWiV!

TWiV 379: A mouse divided

TWiVOn episode #379 of the science show This Week in Virology, Scott Tibbetts joins the TWiVirate to describe his work on the role of a herpesviral nocoding RNA in establishment of peripheral latency, and then we visit two last minute additions to the Zika virus literature.

You can find TWiV #379 at microbe.tv/twiv, or listen below.

Click arrow to play
Download TWiV 379 (85 MB .mp3, 115 min)
Subscribe (free): iTunesRSSemail

TWiV 378: Herpes plays DUBstep

TWiVOn episode #378 of the science show This Week in Virology, Greg Smith joins the TWiVirate to reveal how his lab discovered a switch that controls herpesvirus neuroinvasion, and then we visit the week’s news about Zika virus.

You can find TWiV #378 at microbe.tv/twiv, or you may listen below.

Click arrow to play
Download TWiV 378 (87 MB .mp3, 119 min)
Subscribe (free): iTunesRSSemail

TWiV 369: Camel runny noses and other JNK

On the latest episode of the science show This Week in Virology, a swarm of virologists discusses testing of a MERS coronavirus vaccine for camels, and how a neuronal stress pathway reactivates herpes simplex virus.

You can find TWiV #369 at www.microbe.tv/twiv.

TWiV 362: Gotta catch ’em all

On episode #362 of the science show This Week in Virology, the virus virtuosos, with their usual verve, illuminate a new method to identify all the viral nucleic acids in a sample, and regulation of viral gene expression by codon usage.

You can find TWiV #362 at www.microbe.tv/twiv.

TWiV 358: Virology and proteomics with Ileana Cristea

On episode #358 of the science show This Week in Virology, Vincent meets up with Ileana at Princeton University to talk about how her laboratory integrates molecular virology, mass spectrometry-based proteomics, and bioinformatics to unravel the interplay between virus and host.

You can find TWiV #358 at www.microbe.tv/twiv.

TWiV 348: Chicken shift

On episode #348 of the science show This Week in Virology, Vincent and Rich discuss fruit fly viruses, one year without polio in Nigeria, and a permissive Marek’s disease viral vaccine that allows transmission of virulent viruses.

You can find TWiV #348 at www.microbe.tv/twiv.

TWiV 339: Herpes and the sashimi plot

On episode #339 of the science show This Week in Virology, tre TWiV amici present three snippets and a side of sashimi: how herpesvirus inhibits host cell gene expression by disrupting transcription termination.

You can find TWiV #339 at www.microbe.tv/twiv.

Treatment of Ebola virus infection with brincidofovir

brincidofovirThe Liberian man who was diagnosed with Ebola virus infection after traveling to Dallas, Texas, was treated with an antiviral drug called brincidofovir. This drug had originally been developed to treat infections with DNA-containing viruses. Why was it used to treat an Ebola virus infection?

Brincidofovir (illustrated) is a modified version of an antiviral drug called cidofovir, which inhibits replication of a variety of DNA viruses including poxviruses and herpesviruses. When cidofovir enters a cell, two phosphates are added to the compound by a cellular enzyme, producing cidofovir diphosphate. Cidofovir is used by viral DNA polymerases because it looks very much like a normal building block of DNA, cytidine. For reasons that are not known, incorporation of phosphorylated cidofovir causes inefficient viral DNA synthesis. As a result, viral replication is inhibited.

Cidofovir was modified by the addition of a lipid chain to produce brincidofovir. This compound (pictured) is more potent, can be given orally, and does not have kidney toxicity, a problem with cidofovir. When brincidofovir enters a cell, the lipid is removed, giving rise to cidofovir. Brincidofovir inhibits poxviruses, herpesviruses, and adenoviruses, and has been tested in phase 2 and 3 clinical trials. The antiviral drug is being stockpiled by the US for use in the event of a bioterrorism attack with smallpox virus.

Ebola virus is an RNA virus, so why was brincidofovir used to treat the Dallas patient? According to the drug’s manufacturer, Chimerix,  with the onset of the Ebola virus outbreak in early 2014, the company provided brincidofovir, and other compounds, to the CDC and NIH to determine if they could inhibit virus replication. Apparently brincidofovir was found to be a potent inhibitor of Ebola virus replication in cell culture. Based on this finding, and the fact that the compound had been tested for safety in humans, the US FDA authorized its emergency use in the Dallas patient.

Unfortunately the Dallas patient passed away on 8 October. Even if he had survived, we would not have known if the compound had any effect. Furthermore, the drug is not without side effects and these might not be tolerated in Ebola virus-infected patients. It seems likely that the drug will also be used if other individuals in the US are infected.

Looking at the compound, one could not predict that it would inhibit Ebola virus, which has an RNA genome. RNA polymerases use different substrates than DNA polymerases – NTPs versus dNTPs. NTPs have two hydroxyls on the ribose sugar, while dNTPs have just one (pictured). The ribose is not present in cidofovir, although several hydroxyls are available for chain extension. I suspect that the company was simply taking a chance on whether any of its antiviral compounds in development, which had gone through clinical trials, would be effective. This procedure is standard in emergency situations, and might financially benefit the company.

Update: The NBC news cameraman is being treated with brincidofovir in Nebraska.