Role of the herpesvirus telomeric repeats and the protein U94 in human herpesvirus 6 integration [thesis]

Nina Wallaschek, Universitätsbibliothek Der FU Berlin, Universitätsbibliothek Der FU Berlin
Human herpesvirus 6 (HHV-6) is a betaherpesvirus related to the human cytomegalovirus. It is the causative agent of roseola infantum, a febrile illness in infants, and has a seroprevalence of over 90 % worldwide. Upon primary infection, HHV-6 establishes a persistent infection in the host for life termed latency, mostly in bone marrow progenitor cells, monocytes and macrophages. Reactivation from latency preferentially occurs in immunocompromised individuals and is associated with several
more » ... es including encephalitis, multiple sclerosis, graft rejection as well as a more rapid AIDS progression. HHV-6 has previously been shown to integrate its genetic material into telomeres of human chromosomes, a mechanism that allows vertical transmission of the virus via the germline, resulting in individuals that harbor the integrated virus in every single cell of their body. This condition is termed ciHHV-6 (chromosomally integrated HHV-6) and is present in roughly 1 % of the human population. The molecular mechanism and the factors involved in HHV-6 integration remain completely unknown. Intriguingly, HHV-6 and several other herpesviruses harbor arrays of telomeric repeats (TMRs) at their genome termini that are identical to human telomere sequences. The TMRs in HHV-6 have been termed perfect TMRs (pTMRs) and imperfect TMRs (impTMRs), and have been proposed to facilitate homologous recombination (HR). Furthermore, HHV-6 encodes the U94 gene that contains all conserved domains of the Rep recombinase of Adeno-associated virus 2 (AAV-2). Expression of U94 restores replication of a Rep-deficient AAV-2, suggesting that both proteins have similar functions. Indeed, recently it was confirmed that a purified MBP-U94 fusion protein has DNA-binding, ATPase, helicase and exonuclease activities as described for Rep. However, the actual role of U94 and the TMRs in HHV-6 replication and integration remains elusive. To determine whether the TMRs are involved in HHV-6 integration, I deleted the two distinct sets of TMRs, individually or [...]
doi:10.17169/refubium-15431 fatcat:7fv5eazrmfftdn6mvhxyfuc7l4