Virus envelope glycoprotein targeting bispecific T cell engager protects mice from lethal severe fever with thrombocytopenia virus infection

Severe fever with thrombocytopenia syndrome virus (SFTSV) causes a highly fatal disease with no approved antiviral therapy. This study first analyzed peripheral T cell responses in SFTS patients and found that fatal cases showed marked T cell depletion, reduced cytotoxicity, and severe exhaustion, particularly in CD4⁺ T cells. These findings suggest that impaired T cell immunity contributes to disease severity. To restore antiviral T cell function, they developed a bispecific T cell engager (BiTE) targeting CD3 and the SFTSV envelope glycoprotein Gn. In vitro assays demonstrated that the 3A5 BiTE efficiently redirected human T cells to eliminate SFTSV-infected cells and significantly reduced viral replication. Blocking IFN-γ largely abolished this antiviral effect, whereas inhibition of granzyme B or perforin had minimal impact, indicating an IFN-γ–dependent mechanism. In a lethal mouse model, 3A5 BiTE treatment markedly improved survival and reduced viral loads in serum and organs. BiTE therapy also altered immune cell composition, increasing functional T cells while reducing inflammatory neutrophils and regulatory T cells. These results demonstrate that virus-specific BiTEs can revitalize T cell immunity and provide effective protection against lethal SFTSV infection.
(MN)