Human Herpes Virus Type 6B (HHV-6B, Z29)

Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were thought to be two variants of the same virus, HHV6. Despite a high degree of overall genetic sequence homology (~90%), HHV-6A and HHV-6B are now recognized as two different viruses. Here, the researchers show that both viruses can infect different types of neural cells (i.e., glial cells and neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. Immunofluorescence revealed that HHV-6A and HHV-6B were able to efficiently infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, both viruses appeared unable to infect GAD67-containing cells (i.e., GABAergic neurons). qPCR assays also revealed differences in the expression of immune factors (e.g., cytokines) in cells infected with HHV-6A and HHV6-B. These data, along with morphological and image analyses of infected differentiated neural stem cell cultures, suggest that while HHV-6B may have a greater chance of spreading, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection endpoint. Overall, the results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, but neither virus can efficiently infect GABAergic cells.

To determine whether HHV-6A or HHV-6B preferentially infects specific neurotransmitter phenotypes of neurons, differentiated neurons were co-labeled with neurotransmitter-specific antibodies. For glutamatergic cells, an anti-VGluT1 fluorescent antibody system was used to target the vesicular glutamate transporter (VGluT1), a characteristic protein found in glutamatergic neurons. Simultaneous staining with DAPI and anti-gB fluorescent probe detection showed that VGluT1-positive cells coincided with the anti-gB fluorescent signal in dHNSCs infected with HHV-6A (Figure 1, row A) or HHV-6B (Figure 1, row B). This indicates that both roseoloviruses can infect glutamatergic cells. Among cells identified as glutamatergic (i.e., VGluT1-positive) in mixed cultures, 96% (N=6, p=0.0004) and 73% (N=6, p=0.0005) were gB-positive in HHV-6A and HHV-6B infections, respectively.

Figure 1. Fluorescence microscopy images of dHNSC treated with immunofluorescent antibodies and a fluoro-dye at PDD13: Glutamatergic neurons. (Bahramian E, et al., 2022)