Latency, Integration, and Reactivation of Human Herpesvirus-6

Abstract

Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation. In about 1% of the human population, human herpes virus-6 (HHV-6) integration into germline cells allows the viral genome to be passed down from one generation to the other; this condition is called inherited chromosomally integrated HHV-6 (iciHHV-6). This review will cover the history of HHV-6 and recent works that define the biological differences between HHV-6A and HHV-6B. Additionally, HHV-6 integration and inheritance, the capacity for reactivation and superinfection of iciHHV-6 individuals with a second strain of HHV-6, and the role of hypomethylation of human chromosomes during integration are discussed. Overall, the data suggest that integration of HHV-6 in telomeres represent a unique mechanism of viral latency and offers a novel tool to study not only HHV-6 pathogenesis, but also telomere biology. Paradoxically, the integrated viral genome is often defective especially as seen in iciHHV-6 harboring individuals. Finally, gaps in the field of HHV-6 research are presented and future studies are proposed.

Keywords: HHV-6; human herpesvirus-6; immune tolerance; inherited herpesvirus; integration; latency; superinfection; telomere.

Figure 1

Genome organization of human herpesvirus-6 (HHV-6). Solid lines represent the unique length (U) regions of the genome, boxed regions represent repetitive elements of the genome, and the black boxes represent the perfect telomere repeats, while the gray boxes represent the imperfect telomere repeats. DR_L: Direct repeat left; DR_R: Direct repeat right; pac1, pac2: Packaging signals; R0–3: Repetitive elements.

Figure 2

Model for integration and reactivation of HHV-6. The linear genome of HHV-6 integrates into the telomeres of the host chromosome, and during reactivation the integrated genome is liberated from the host chromosome, forming a circular intermediate. Rolling circle replication of the circular intermediate generates concatemers of the viral genome.

Figure 3

Possible integration configurations of the HHV-6 genome. (A) The HHV-6 genome contains four telomere-like repeats flanking the direct repeats; (B) Integration of the HHV-6 genome by recombination with the host telomeres can potentially occur at either of the four telomere repeats and five possible integration configurations may be generated.