Mouse hepatitis virus (MHV; murine coronavirus[M-CoV]) causes meningoencephalitis, myelitis, and optic neuritis followed by axonal loss and demyelination. This murine virus is used as a common model to study both acute and chronic virus-induced demyelination in the central nervous system. Studies with recombinant MHV strains that differ in the gene encoding the spike protein have demonstrated that the spike has a role in both MHV pathogenesis and retrograde axonal transport. Fusion peptides (FPs) in the spike protein play a key role in MHV pathogenesis. In a previous study of the effect of deleting a single proline residue in the FP of a demyelinating MHV strain, we found that two central, consecutive prolines are important for cell-cell fusion and pathogenesis. The dihedral fluctuation of the FP was showed to be repressed whenever two consecutive prolines (PP) were present, in contrast to the presence of a single proline (P) in the chain. Using this prolinedeleted MHV strain, here we investigated whether intracranial injection of this strain can induce optic neuritis by retrograde axonal transport from the brain to the retina through the optic nerve. We observed that the prolinedeleted recombinant MHV strain is restricted to the optic nerve, is unable to translocate to the retina, and causes only minimal demyelination and no neuronal death. We conclude that an intact proline dyad in the FP of the recombinant demyelinating MHV strain plays a crucial role in translocation of the virus through axons and subsequent neurodegeneration https://www.jbc.org/cgi/

Objective: Interferon-alpha (IFN-a) has been associated with excessive immune activation and dysfunction during HIV-1 infection. However, evidence suggests specific IFN-a subtypes may be beneficial rather than detrimental. This study compared the effects of treatment with two different IFN-a subtypes on indicators of T-cell activation and dysfunction during HIV-1 infection.Design: Humanized mice were infected with HIV-1 for 5 weeks and then treated with two different IFN-a subtypes for an additional 3 weeks. Splenic T cells were assessed both immediately posttreatment and again 6 weeks after treatment cessation.Methods: HIV-1 infected triple-knockout bone marrow-liver-thymus mice received daily intraperitoneal injections of either IFN-a14 or the clinically approved subtype, IFN-a2. T cells were analysed directly ex vivo for indicators of activation and dysfunction or stimulated to determine their proliferative capacity and ability to produce functional mediators.Results: Unlike IFN-a2, IFN-a14 treatment reduced viremia and resulted in less activated CD4 þ T cells and a lower naı ¨ve to effector CD8 þ T-cell ratio. Despite exhibiting a reduced proliferative response, the frequency of CD8 þ T cells from IFN-a14 treated mice that produced functional mediators and expressed markers of dysfunction was more similar to healthy controls than untreated and IFN-a2 treated mice. Frequencies of exhaustion marker expression remained higher in untreated and IFN-a2 treated mice 6 weeks posttreatment despite similar viral loads between groups at this timepoint.Conclusions: Treatment with different IFN-a subtypes had distinctive effects on T cells during HIV-1 infection. IFN-a14 was associated with fewer indicators of T-cell dysfunction whereas IFN-a2 treatment had little impact.

Small animal models that accurately model pathogenesis of SARS-CoV-2 variants are required for ongoing research efforts. We modified our human immune system mouse model to support replication of SARS-CoV-2 by implantation of human lung tissue into the mice to create TKO-BLT-Lung (L) mice and compared infection with two different variants in a humanized lung model. Infection of TKO-BLT-L mice with SARS-CoV-2 recapitulated the higher infectivity of the B.1.1.7 variant with more animals becoming infected and higher sustained viral loads compared to mice challenged with an early B lineage (614D) virus. Viral lesions were observed in lung organoids but no differences were detected between the viral variants as expected. Partially overlapping but distinct immune profiles were also observed between the variants with a greater Th1 profile in VIDO-01 and greater Th2 profile in B.1.1.7 infection. Overall, the TKO-BLT-L mouse supported SARS-CoV-2 infection, recapitulated key known similarities and differences in infectivity and pathogenesis as well as revealing previously unreported differences in immune responses between the two viral variants. Thus, the TKO-BLT-L model may serve as a useful animal model to study the immunopathobiology of newly emerging variants in the context of genuine human lung tissue and immune cells.