Researchers led by Yasuko Mori of Kobe University in Japan have developed an animal model that will be useful for studying the pathogenicity of HHV-6B in conditions such as acute GVHD and idiopathic pneumonia
Although both CD46 transgenic (Reynaud 2013) and a humanized mouse model (Tanner 2013) exist for HHV-6A, a model for HHV-6B has been more challenging because HHV-6B utilizes the CD134 receptor that appears only on activated cells. The Japanese group achieved a high ratio of activated human T-cells with an intraperitoneal injection of 4-6 x 106 stimulated human cord blood mononuclear cells (CBMCs) into immunodeficient humanized mice. The CBMC transfer was followed by a “remarkable increase” in the number of activated T-cells expressing CD134, creating ideal conditions for HHV-6B infection.
The clinical result in the mice was a condition similar to acute graft-versus-host disease (GVHD) with HHV-6B replication in all main organs, but especially high in the spleen and lungs. The investigators also observed an increase in inflammatory cytokines and chemokines in HHV-6B infected mice similar to the profile found in children with primary HHV-6B infection and to in vitro infection.
The authors propose that the relationship between HHV-6B and GVHD may be recursive; HHV-6B increases the risk of GVHD, which in turn may increase T-cell-production and expression of CD134. Their study also confirmed a “tight correlation” between the expression of CD134 and HHV-6B reactivation/replication after allogenic HSCT.
There were relatively high secretions of IL-6, IL-8, CCL2 and CCL8 in the early phase of infection. HHV-6B showed significant organ-tropism to the spleen and the lungs (~10,000 copies/ng total DNA 8 days post-infection). The observation of high levels of the virus in lung tissues supports previous studies reporting a role for HHV-6B in various lung pathologies (Seo 2015; Hill 2019; Zhou 2019).
An HHV-6/7 homolog, murine roseolovirus (previously known as murine thymic virus), has many similarities to HHV-6B and has been shown to cause T cell depletion (Patel 2017) as well as increased acute GVHD and lung fibrosis in a murine bone marrow transplant model (Zhou 2019).
The authors plan to use their HHV-6B model to further elucidate viral pathogeneses and to evaluate HHV-6B specific antivirals.
Read the full-text: Wang 2019