Project Grant R21AI186385

STUDIES ON INHERITED CHROMOSOMALLY INTEGRATED HHV-6 WITH PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELLS - PROJECT SUMMARY HUMAN HERPESVIRUS 6A AND HUMAN HERPESVIRUS 6B, COLLECTIVELY TERMED HHV-6A/B, ARE UBIQUITOUS VIRUSES THAT PERMANENTLY INFECT MOST HUMANS FROM AN EARLY AGE. INITIAL HHV-6A/B INFECTION MAINLY OCCURS FROM THE CONTACT OF INFECTED SALIVA OR NASAL MUCUS WITH THE RESPIRATORY TRACT. HOWEVER, HHV-6A/B GENOME CAN BE MAINTAINED GENERATION TO GENERATION THROUGH INHERITANCE, WHICH IS MEDIATED BY THE INTEGRATION OF HHV-6A/B GENOMES INTO THE TELOMERES OF HOST CELL CHROMOSOMES. INHERITED CHROMOSOMALLY INTEGRATED HUMAN HERPESVIRUS 6 (ICIHHV-6) IS SEEN IN 1-2% OF EUROPEAN AND US POPULATIONS AND 0.6% OF PEOPLE IN JAPAN. IN THESE HUMAN POPULATIONS, THE HHV-6 GENOME IS INTEGRATED INTO THE TELOMERE OF A SINGLE CHROMOSOME IN EVERY NUCLEATED CELL IN THE BODY. THESE INTEGRATED VIRUSES REACTIVATE FROM THE INTEGRATED CHROMOSOME TO PRODUCE VIRAL PROGENIES. REACTIVATION OF ICIHHV- 6 IS SUGGESTED TO BE ASSOCIATED WITH MANY DISEASE DEVELOPMENTS THAT INCLUDE ENCEPHALITIS, SPONTANEOUS ABORTIONS, PRE-ECLAMPSIA, ANGINA PECTORIS, AND EXACERBATION OF GRAFT-VERSUS-HOST DISEASE FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION. ACCUMULATING EVIDENCE HAS ALSO SUGGESTED THE NEUROVIRULENCE OF HHV- 6A/B INFECTION WITH SEVERAL IMPORTANT NEUROLOGICAL DISORDERS. IN PARTICULAR, EVIDENCE INDICATES THAT HHV-6B REACTIVATION CAN CAUSE ACUTE LIMBIC ENCEPHALITIS IN IMMUNOCOMPROMISED PATIENTS, AND FREQUENT VIRAL REACTIVATION CYCLES RESULT IN TEMPORAL LOBE EPILEPSY. HOWEVER, A LACK OF SUITABLE IN VITRO MODELS TO EVALUATE HHV-6A/B REACTIVATION FROM THE INTEGRATED VIRAL GENOME IN NEURAL CELLS, LIMITS OUR STUDY DESIGNS. THIS IS BECAUSE, FOR DISEASES OF THE CENTRAL NERVOUS SYSTEM, THE AFFECTED TISSUE IS CHALLENGING TO ACCESS FOR STUDY IN LIVING PATIENTS. SUCH IN VITRO TISSUE CULTURE MODELS WILL EXAMINE RISKS OF HARBORING ICIHHV-6 IN DISEASE DEVELOPMENTS AND FACILITATE MOLECULAR ANALYSIS OF ICIHHV-6 REACTIVATION/REPLICATION FROM INTEGRATED HOST CHROMOSOMES. LIKE OTHER VIROLOGY RESEARCH, ESTABLISHING AN IN VITRO CULTURE MODEL IS VITAL TO IDENTIFY ESSENTIAL CELLULAR OR VIRAL TARGETS FOR FURTHER THERAPEUTIC DEVELOPMENT. HERE, WE REQUEST FUNDING TO ESTABLISH CELL MODELS TO STUDY ICIHHV-6 REACTIVATION. WE WILL GENERATE INDUCED PLURIPOTENT STEM CELLS (IPSCS) AND DIFFERENTIATE THEM INTO NEURAL STEM CELLS. WITH THE ESTABLISHED RESOURCES, WE WILL EXAMINE HOW AND WHEN ICIHHV-6 REACTIVATION IS TRIGGERED. WE WILL TEST WHAT PHYSIOLOGICAL CELL DIFFERENTIATION PROCESSES TRIGGER ICIHHV-6 REACTIVATION. WE WILL COMPLETE THE TASKS WITH ONGOING INTERNATIONAL COLLABORATION, AND DEVELOP ESSENTIAL RESOURCES FOR HHV-6A/B RESEARCHERS.