Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Abstract

Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra-and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra-and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

“…To date, no evidence of productive HHV-6B infection has been obtained for neural stem cells, astrocytes and oligodendrocytes, [67][68][69] suggesting that CNS reactivation depends on systemic HHV-6 reactivation. Autopsy studies of patients who died with HHV-6 encephalitis have shown the hippocampus has strong reactivity against HHV-6, 9,70 and HHV-6 has displayed tropism for astrocytes in the hippocampus.…”

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

“…As HHV-6 is known to be neurotropic in humans and to infect both human astrocytes and oligodendrocytes (22)(23)(24)(25), we next analyzed the permissiveness of primary brain glial cultures, which mostly contain astrocytes and, to a lesser extent, oligodendrocytes and microglial cells (data not shown), to HHV-6 infection. These cultures were obtained from either CD46-cyt1 mice, expressing the cyt1 isoform of CD46, or wild-type littermate con-trols (Fig.…”

“…CD46 expression in humans is ubiquitous (19); therefore, it provides a wide range of potentially susceptible cell types for HHV-6 infection. Although lymphocytes are known as the main target cells, several CNS cell types, including astrocytes and oligodendrocytes, have been successfully infected by HHV-6A and, with lower efficiency, by HHV-6B (20)(21)(22)(23)(24)(25)(26)(27). Recently, CD134 (OX40), a member of the tumor necrosis factor (TNF) receptor superfamily that was expressed on activated T lymphocytes, has been identified as a receptor molecule for HHV-6B (28).…”

Human CD4+T Cell Response to Human Herpesvirus 6

“…The four remaining peptides, 083s, 1017, 1106, and 1211s, have significant homology with HHV-7 (see Table S2). HHV-6A but not HHV-6B is characterized by neurotropism (2,21,33), and so it would be advantageous to have reagents to corroborate if relapses in diseases like MS are associated with immune responses to HHV-6A rather than HHV-6B, as suggested by Fogdell-Hahn et al (25). Sequence analysis of the 11 epitope peptides and cross-reactivity studies (Fig.…”