T cells transiently expressing TCRs against HBV show antiviral activity in HBV/HDV co-infected humanized mice

Question:

Co-infection with hepatitis B and D viruses (HBV/HDV) causes the most severe form of viral hepatitis and is associated with a higher risk of cirrhosis, decompensation and cancer. We showed that adoptive transfer of human T cells engineered to transiently express HBV-specific T cell receptors (TCR) using mRNA electroporation reduces HBV infection in human liver chimeric uPA/SCID/ILγR2 (USG) mice (Kah, JCI 2017). Aim of this study was to assess the antiviral activity of T cells transiently expressing HBV-specific TCRs in the setting of HBV/HDV coinfection using USG mice.

Methods:

PBMCs isolated from healthy human blood were activated in vitro (IL2 600 IU/ml CD3/CD28 beads for one week), electroporated with TCR mRNA HBV-s183 (restricted by HLA-A2) and tested both against HEPG-2-NTCP HBV/HDV infected cells and in vivo (3 injections in 12 days) using uninfected and HBV/HDV-infected, haplotype matched (HLA-A2) humanized mice. Serological, intrahepatic markers and gene expression were determined by qRT-PCR and immunofluorescence.

Results:

HBV-TCR redirected T cells reduced HDV-RNA (20% reduction) in HBV/HDV coinfected HepG2-NTCP cells. Three injections of HBV-TCR redirected T cells in HBV/HDV co-infected mice caused progressive reduction of HBV viremia in 12 days (n = 4; median 0.9log), which was comparable to the decrease determined in HBV mono-infected mice (n = 3; median 1log). Also intrahepatic HBV transcripts appeared lower in treated mice in comparison to untreated HBV/HDV mice (mean 68%). These effects were accompanied by a clear infiltration of human lymphocytes in the liver of infected mice, increase of ALT levels and a strong induction of human inflammatory cytokines and markers (e.g. h-GzmB > 3log, h-IFN-γ > 2log RNA increase). Of note, HDV viremia also decreased within 12 days (n = 4; median 0.7log), although the magnitude of HDV decrease strongly varied, ranging from no decrease in the mouse harboring the lowest level of HDV infection at baseline, to a strong HDV decrease (2log viremia reduction) in the mouse displaying the highest levels of HDV infection before treatment.

Conclusions:

our data show that in the setting of HBV/HDV coinfection human T cells redirected to express HBV-specific TCRs displayed anti HBV activities comparable to that determined in HBV mono-infection. Moreover, HBV-redirected T cells also reduced HDV loads and the amplitude of anti-HDV effects appeared to correlate to the amount of HBV/HDV co-infected cells present at baseline. Aware of the paucity of anti-HDV treatments available, T cells transiently expressing HBV-specific TCRs may represent an attractive therapeutic option to lower the amount of coinfected cells.