Graduation Year


Document Type




Degree Granting Department

Medical Sciences

Major Professor

Peter G. Medveczky


Chronic Fatigue Syndrome, HHV-6, Inherited Herpesvirus Syndrome, Telomere, Virus Integration


Human Herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are ubiquitous betaherpesviruses. Both viruses are associated with a variety of adult disorders including neurological disorder, such as multiple sclerosis and chronic fatigue syndrome. HHV-6 viruses are capable of establishing latency by integration into the telomeres of the host chromosome and are transmitted in a Mendelian manner in approximately one percent of the population. To date little is known about the immunological and neurological consequences of HHV-6 inheritance. This study focused on a unique population of individuals that inherited HHV-6 and present with chronic fatigue-like symptoms, including hypersomnia, generalized fatigue, headache, and short term and long term memory impairment. The central hypothesis of this study was that active replication of HHV-6 correlates with patient symptoms. To address this aim we first looked at the reactivation of integrated HHV-6 in vitro by inducing viral replication with epigenetic modifiers trichostatin A (TSA), valproic acid, sodium butyrate, and carbamazepine, and found TSA to be an effective method of inducing reactivation of HHV-6 from its integrated form. Additionally, a reactivated HHV-6A virus isolated from a patient with inherited HHV-6 was fully sequenced and the nucleotide and amino acid sequence was compared to that of fully sequenced HHV-6 laboratory strains, as well as the inherited virus. The reactivated virus was found to be very similar to the HHV-6A GS strain; however, there was some divergence at the right end of the viral genome and regions of the genome that do not contain herpesvirus core genes. Interestingly, the sequenced reactivated virus was found to differ from the HHV-6 virus which was inherited. Finally, HHV-6 replication was assessed by performing reverse transcriptase PCR assay for the viral glycoprotein U100 in patients receiving antiviral treatment. Results indicated that short term antiviral treatment was insufficient to abrogate viral replication, while treatment of six weeks or longer eliminated viral mRNA in patient blood samples. Furthermore, sequencing of the viral mRNA and inherited viral DNA indicate that the source of the mRNA detected in patient blood samples was an exogenously acquired HHV-6 virus, as the U100 glycoprotein sequences were not identical. Together these studies indicate that although HHV-6 can be reactivated from its integrated form, individuals in this unique population harbored an exogenous HHV-6 virus, in addition to the inherited virus; we termed this condition inherited herpesvirus syndrome. The fact that these individuals are able to acquire exogenous HHV-6 viruses suggest that there may be some level of immune tolerance or immune dysfunction; we suggest that further studies focus on uncovering the immune response to HHV-6 in individuals with an inherited form of the virus.

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Virology Commons