Is there a new HHV-6 animal model on the horizon?

Seattle group announces the discovery of novel HHV-6 and HHV-7 homologs in pig-tailed macaques

A research project carried out at the Center for Global Infectious Disease Research, with Seattle Children’s Research Institute, has led to the discovery of two novel HHV-6 and HHV-7 homologs in pig-tailed macaques that may soon be used as clinical models of roseolovirus infection. The team, led by Dr. Serge Barcy, identified the virus homologues (named MneHV-6 and MneHV-7) in the saliva of pig-tailed macaques. This finding supports the existence of two distinct roseolovirus lineages, perhaps before the divergence of humans and macaques. The paper has been featured on the Virology Highlights Blog.

Salivary gland tissue stained with the OHV-3 antibody specific for HHV-6 glycoprotein H (p98)

The investigators used Consensus-Degenerate Hybrid Oligonucelotide Primers (CODEHOP) to find the homologs. This technique has proven to be effective in identifying unknown viruses. A blood screen of 283 macaques revealed 10% MneHV-6 DNA positivity and 25% MneHV-7 positivity, with higher prevalences of MneHV-6 in older females and of MneHV-7 in younger males. Levels of MneHV-6 were increased in animals co-infected with MneHV-7, and both viruses were frequently detected in salivary gland and stomach tissues. Co-infection with MneHV-7 was associated with increased MneHV-6 viral loads in blood. “We believe this discovery provides a unique animal model to answer unresolved questions regarding Roseolovirus pathology,” commented Dr. Barcy. “The animal model we proposed to develop is different from previous models since it is based on a natural infection with endogenous viruses, MneHV-6 and MneHV-7, thus avoiding potential pitfalls related to experimental inoculation. In addition, our model provides an opportunity to study in vivo interactions between the two viruses.” he added.

While the existence of roseolovirus homologs in non-human primates had been suggested based on serological data (Higashi 1989), previous attempts to find HHV-6-like sequences in pig-tailed macaques by HHV-6-specific PCR ultimately failed, leading to the assumption that these animals are not commonly infected by a virus related to HHV-6 (Lusso 1994). This study provides the first identification and characterization of two new roseolovirus homologs of HHV-6 and HHV-7 naturally infecting pig-tailed macaques (Macaca nemestrina), one of the major species maintained at the Washington National Primate Research Center. Pig-tailed macaques are commonly used as “non-human primate” models for biomedical research, since they develop disease pathologies similar to those seen in humans. Investigators at the Pasteur Institute previously identified HHV-6 simian homologues in chimpanzee, mandrill and drill monkeys (Lacoste 2000-2005).

In 2013, a group at NINDS/NIH led by Steve Jacobson reported that they were successfully able to infect marmosets with human HHV-6A and HHV-6B (Leibovitch 2013). They found that marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while HHV-6B infected marmosets were asymptomatic and generated much lower antibody responses. Earlier this year Branka Horvat’s team at the International Center for Infectiology Research in Lyon, France, announced their successful development of a transgenic mouse model of HHV-6A infection; their mice express human CD46, a known receptor for HHV-6A. In addition, a group led by Dr. Bradford Berges from Brigham Young University has successfully infected humanized mice with HHV-6A, demonstrating in vivo evidence for both acute and persistent infection.

The photograph accompanying this article depicts salivary gland tissue stained with the OHV-3 antibody specific for HHV-6 glycoprotein H (p98), a monoclonal antibody that was developed by Koichi Yamanishi in Japan and contributed to the HHV-6 Foundation Repository.

For more information, read the full paper