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.

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expressionin vivothat correlates with increased antibody immune response

“…From the whole genome DNA-Seq data available from 650 GTEx individuals, we determined 6 were consistent with iciHHV-6 – 4 iciHHV-6B and 2 iciHHV-6A. These 6 samples had an average normalized depth of coverage across the HHV-6A/B genome that was approximately half (0.45 ± 0.035) that of human housekeeping genes EDAR and beta-globin, consistent with heterozygous iciHHV-6 at the approximate 1% prevalence typically found in human populations (Figure 1A) (23). Of note, no evidence of chromosomally integrated HHV-7 was found (24).…”

The Complete Genome of an Endogenous Nimavirus (Nimav-1_LVa) From the Pacific Whiteleg Shrimp Penaeus (Litopenaeus) Vannamei

“…Little is known about the molecular mechanism underlying such integration because we cannot exclude the possibility that circular Nimav-1_LVa could harbor one short tract of variable length of (TAACC/GGTTA) n microsatellites somewhere between g002 and g276. If so, the integration of Nimav-1_LVa would be through the homology-based recombination, which is adopted in the telomere-specific integration of human herpesvirus HHV-6A, HHV-6B [40][41][42], and chicken lymphotropic alphaherpesvirus Marek's disease virus (MDV) [43,44].…”

Primary infection with human herpes virus type 6, post‐pediatric liver transplantation—A pathogen to remember

“…HHV‐6 infects T cells. Latency is achieved by integration into host telomeres, presumably in macrophages/monocytes . Clinical disease because of reactivation in immune deficient children has been well‐described, especially in bone marrow transplantation recipients …”