Editorial Commentary: Pathogenesis From the Reactivation of Chromosomally Integrated Human Herpesvirus Type 6: Facts Rather Than Fiction

(See the Brief Report by Endo et al on pages 545–8.) Viral latency, defined by the ability of a virus to remain dormant, is a commonly used immune evasion strategy that enables the long-term persistence of viruses within the infected host. On occasion, these viruses come out of latency and initiate their replicative cycles, yielding a progeny of infectious virions favoring viral propagation and dissemination with possible pathogenic outcomes depending on the immunological competency of the host. Among the most successful viruses utilizing latency as a mean of persistence are herpesviruses. Typically, during latency, herpesviruses maintain their genome in the nucleus in the form of an episome (extrachromosomal circular DNA) and express only a handful of proteins (often 1 protein) that ensure episome maintenance and transmission to daughter cells upon cell division. Among the 100 or so herpesviruses infecting vertebrates, a few of them have evolved mechanisms allowing them to integrate their viral genome into the host chromosomes in manners analogous to retroviruses. Example of such viruses include Marek disease virus (an oncogenic chicken herpes virus) and human herpesvirus (HHV) 6A and 6B (reviewed in [1]). HHV-6A and HHV-6B were isolated in 1986 and 1988 [2, 3], respectively, and the first report on chromosomally integrated HHV-6 (ciHHV-6) made in 1993 [4]. Daibata et al were the first to demonstrate vertical transmission of HHV-6 DNA over 3 generations by showing identical HHV-6 integration sites between a patient with acute lymphoblastic leukemia, his son, and his granddaughter, who were otherwise healthy [5]. HHV-6A and HHV-6B integration can take place in several distinct chromosomes, but the integration site invariably takes place at the ends of chromosomes within the telomeric region [6]. Since then, several other cases of ciHHV-6 were reported (reviewed in [1]) and biological consequences of ciHHV-6 discussed [7]. Whether HHV-6 integration was a viral dead end or constitutes a new form of latency remained, for many years, an unanswered fundamental biological question. Using Epstein-Barr virus–immortalized B-cell lines from subjects with ciHHV-6 and various culture conditions, several investigators proved unsuccessful at rescuing infectious HHV-6, although viral gene expression could be demonstrated [5, 8–11]. Using human cell lines, Arbuckle et al provided the first evidence of de novo integration and successful rescue of infectious HHV-6 virions from ciHHV-6–infected cells [12], suggesting that HHV-6 can reactivate once integrated. The first in vivo evidence of reactivation of ciHHV-6 came from Gravel et al, who provided data consistent with transplacentally acquired HHV-6 originating from the transmission of reactivated ciHHV-6 from the mother [13].

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