Human Herpes Virus Type 6A (HHV-6A, GS)

Control of viral infection in the brain involves activation of microglia (brain macrophages that continuously monitor the central nervous system) and production of amyloid-β protein (Aβ) as an antimicrobial molecule. Recent findings suggest that HHV-6A may be involved in Alzheimer's disease (AD). Here, researchers evaluated the effects of HHV-6A infection on microglial Aβ expression and its activation state, which is determined by the expression of TREM2, ApoE, cytokines, and tau protein. They infected microglial cells, in monolayer and human peripheral blood monocyte-derived microglia (PBM-microglia) spheroid 3D model, with HHV-6A cell-free virus inocula with 100 genome equivalents per 1 cell. Efficient infection with HHV-6A was observed. The expression of Aβ 1-42 increased from 3 days after infection, while no significant induction was observed for the expression of Aβ 1-40. HHV-6A infection induced microglial activation (TREM2, IL-1β, ApoE) and migration. Tau secretion began 7 days after infection, and the proportion of phosphorylated forms continued to increase. These results suggest that microglia are tolerant to HHV-6A infection, which can induce Aβ expression and activation state.

Aβ is the main component of neuritic plaques and is one of the more important molecules associated with the pathogenesis of AD. Studies have shown that the presence of HSV-1 and HHV-6 rapidly induces the production of amyloid plaques within 24 to 48 hours. These results support the hypothesis that Aβ deposition and fibrillization may be an innate immune response to pathogens that can protect the brain under normal circumstances. To this end, the researchers evaluated the effect of HHV-6A on the expression of two Aβ isoforms (Aβ1-40 and Aβ1-42) that are more relevant to AD. Aβ1-42 expression increased during HHV-6A infection, and Aβ1-40 expression increased slightly (Figure 1a). Interestingly, immunofluorescence analysis showed that the gp116 late viral antigen co-localized with Aβ1-42 protein expression (Figure 1b), indicating that HHV-6A infection has a direct effect on Aβ1-42 induction.

HHV-6A spheroid infection was monitored by gp116 expression. The researchers confirmed the permissivity of microglia to HHV-6A infection by increased transcription of U42 IE viral genes and expression of gp116 late viral antigen (Figure 1c-e). The analysis also showed that with the increase in gp116 expression, Aβ1-42 expression also increased (Figure 1d). Interestingly, at higher magnification, Aβ deposition could be observed, which was particularly evident at 14 d.p.i. (Figure 1e, left panel).

Figure 1. Beta amyloid expression in HHV-6-infected microglial cells. (Bortolotti D, et al., 2019)