Background: Prophylaxis against HCV infection of the naÏve allograft is integral to efforts to improve outcomes in HCV positive liver transplant recipients. To effectively achieve this, safe and tolerable therapies will be needed in combination. Antigenic region 4a monoclonal antibody (AR4a) targeting HCV E1/E2 glycoprotein complex has demonstrated cross neutralizing activity in-vitro. EGCG, a green tea extract also displays anti-HCV activity possibly by disrupting virion attachment. We examined the ability of EGCG and AR4a in combination to inhibit HCV infection in-vitro and in-vivo.
Methods: Using the JFH-1 HCV cell culture(HCVcc) model the anti-HCV activity of these agents was tested alone and in combination. HCV constructs expressing E1/E2 from genotypes 1-6 were tested. AR4a was pre-incubated with virus for one hour pre-infection, EGCG was added simultaneous with infection of human hepatoma 7.5 cells. NS5a immunostaining was performed at 48 hours post-infection. We utilised the uPA-SCID humanized mouse liver model to assess the tolerability and anti-HCV activity of these agents in vivo.
Results: In the HCVcc model both AR4a and EGCG dose dependently inhibited HCV infection. The IC50 for EGCG was 10mcg/ml. High dose AR4a (10mcg/ml) inhibited genotype 1a and 2a infection by 94% and 68.7% respectively. Combining the agents at these doses significantly inhibited infection further, effectively achieving complete inhibition of infection (Genotype 1a: p=0.023, p<0.0001 for the combination vs. AR4a mAb and EGCG alone respectively; Genotype 2a: p=0.02, p<0.001 respectively). This combination robustly protected against infection across all genotype constructs tested (1-6). High dose EGCG (200mg/kg) by gavage for 14 days was well tolerated by uPA-SCID mice transplanted with human hepatocytes. In HCV challenge experiments AR4a (alone and combined with EGCG) protected mice against infection initially (p=0.01); EGCG alone did not protect against establishment of HCV infection.
Conclusion: Low dose EGCG at concentrations achievable in vivo combined with high dose AR4a monoclonal antibody can effectively prevent HCV infection in vitro. This protection is replicated across HCV genotypes 1-6. These agents are safe and well tolerated in a humanized liver mouse model. Combined they may represent a potential novel strategy to employ peri-transplant to prophylax against HCV re-infection.
To cite this abstract in AMA style:O'Shea D, Law J, Egli A, Lisboa L, Kumar D, Tyrrell L, Houghton M, Kneteman N, Humar A. Novel Strategy To Prevent HCV Re-Infection Post Liver Transplantation: Anti-E1/E2 Monoclonal Antibody and Epigallocatechin Gallate (EGCG) in Combination, A [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/novel-strategy-to-prevent-hcv-re-infection-post-liver-transplantation-anti-e1e2-monoclonal-antibody-and-epigallocatechin-gallate-egcg-in-combination-a/. Accessed September 24, 2020.
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