HHV-6A/B in brain disease: proposed criteria for establishing causation

A comprehensive 10,000- word review of HHV-6A/B in brain disease was published in a high-impact medical journal, Clinical Microbiology Reviews.  The authors were Anthony Komaroff, MD, of Harvard University Medical School, Philip E. Pellet, PhD of  Wayne State University and Steven Jacobson, PhD of NINDS/NIH

The group summarized the literature focusing on what is known about the role of HHV-6B in febrile seizures, febrile status epilepticus and mesial temporal lobe epilepsy, as well as the role of HHV-6A/B in multiple sclerosis and Alzheimer’s disease and proposed criteria for linking ubiquitous infectious agents to neurologic disease.

The authors propose the following criteria for establishing a causal role for HHV-6 in any disease:

  • HHV-6A/B nucleic acid is present in diseased tissue, in most cases, in higher abundance than in non-diseased tissue (by qPCR or other means).
  • The amount of HHV-6A/B nucleic acid in diseased tissue or blood, and/or antibody levels, correlates with the severity of the disease.
  • HHV-6A/B nucleic acid is demonstrated in cells relevant to disease pathology.
  • HHV-6A/B mRNA (by RT-PCR, or other means) and antigens by immunohistochemistry are present in diseased tissue.
  • Exposure to and then presence of the viruses and their gene products in affected tissue precede the development of the disease (temporal relationship).
  • Infectious agents other than HHV-6A/B are not generally detected in diseased tissue in a substantial number of cases.
  • There are cellular and/or humoral immune responses to HHV-6A/B in diseased tissue and/or in blood, and these responses correlate with the severity of the disease.
  • HHV-6A/B affect cellular function in diseased tissue in a manner able to cause or augment the disease pathology (in vitro or in vivo studies).
  • Specific antiviral therapy both reduces viral load in diseased tissue or blood and is followed by clinical improvement.

The authors note that for febrile seizures, febrile status epilepticus and mesial tempora lobe epilepsy, several of the factors have been met, but that pinpointing the virus  in the affected areas of the brain are nearly impossible to obtain since there is no justification to obtain brain biopsies. Also no antiviral trials have been conducted to determine whether therapy would improve the outcome of the disease.

For multiple sclerosis, most of the criteria except an antiviral trial have been met, although the results from multiple laboratories have not been consistent.

Regarding Alzheimer’s disease, the authors propose that much deeper sequencing than what has been employed to date, as well as more specific and sensitive probes in the brain tissues from AD patients.

The group also developed principles to guide future research

Read the full paper: Komaroff 2020