The role of Human Herpesvirus6 and Multiple Sclerosis

Several herpesviruses have been suggested to mediate susceptibility to MS, but for several reasons, HHV6, which is actually two similar but distinct viruses; 6A and 6B, is preferable as the first target to study. These viruses usually infect people often in infancy, so the immune response to other herpesviruses may be influenced by the response to HHV6. Unlike the other herpesviruses, HHV6 can integrate into human chromosomes and in some cases is passed from parent to child and can be studied like a genetic trait. Study of how often this chromosomal integration of HHV6 (ciHHV6) is seen in MS patients would allow determination if either virus has an impact on MS susceptibility, clinical course and therapeutic response, among other things. The key is to test for ciHHV6AB in large MS datasets. Current methods are not optimal as they are geared toward detecting the infective virus, or in verifying ciHHV6 when it is suspected, are costly, and do not discriminate between HHV6A & HHV6B. The goal of this project is to develop and optimize a cost-effective genetic test for this. Once obtained, the test can be applied to the large MS case-control cohorts to clarify the role of HHV6A and HHV6B in MS.
The first step is to establish positive and negative test conditions. By obtaining commercially available samples of chromosomal DNA from persons with or without ciHHV6 and samples of HHV6AB viral DNA will allow us to produce the test panels. The next step will be to evaluate the sensitivity and specificity of a number of different published methods to detect the viruses in these panels. Once found, these will be compared to human chromosome markers to find which are compatibile to quantitate human genes. This is done because when a person has ciHHV6AB in their genome, the virus will be present in the same amount as the human genes. In the case of persons only infected with the virus, but where it has not integrated into the chromosome, it is present in far fewer copies than the human genes.
The next step is to test robustness: different concentrations of HHV6A of HHV6B viral DNA as “noise” will be added to establish critical thresholds between true ciHHV6 samples and samples contaminated with HHV6 viral DNA to allow distinction. A workable method in hand, we should begin testing on MS disease cohorts, like the Sardinian one we previously worked on.

Members:
Michael Bernard Whalen (Principal investigator)