Predictive efficacy of SCID-hu mouse models for treatment of human cytomegalovirus infections

Abstract

There are few animal models to evaluate the in vivo activity of new compounds against human cytomegalovirus (HCMV) infections, as virus replication is largely limited to human cells. In our studies, we have utilized SCID mice implanted with human tissue (SCID-hu) and inoculated with HCMV as models for infections of the eye or visceral organs in an immunocompromised host. For the ocular model, fetal human retinal tissue was implanted in the anterior chamber of the SCID mouse eye and inoculated 6-9 weeks later with 2,000-7,500 plaque-forming units (pfu) of HCMV. In the second model, fetal thymus and liver (thy/liv) tissue was implanted under the kidney capsule of SCID mice and inoculated 12-14weeks later with 2,200-9,000 pfu of HCMV. At various times after infection, implant tissues were removed, homogenized, and HCMV titres quantified by plaque assay. The replication of the Toledo strain of HCMV in both models was similar in that viral titres increased through day 21, remained high through day 35, and then gradually decreased. To validate the two models, the efficacy of ganciclovir (GCV) and cidofovir (CDV) was determined in both ocular and thy/liv model implants. In SCID-hu retinal tissue, once daily intraperitoneal (i.p.) treatment with 33 mg GCV per kg significantly reduced viral titres (2-20-fold) between 14 and 28 days after infection. In SCID-hu thy/liv implants, the same treatment regimen reduced viral replication either completely or by 3-5 log10. In retinal implant tissue, i.p. treatment with 25 mg CDV per kg once daily for 14 days, followed by three times weekly for the next 14 days, reduced viral titres by 2-3 log10 between 10 and 42 days after infection. In comparison, once daily i.p. administration of 30 mg CDV per kg completely inhibited HCMV replication in thy/liv implants. These results indicate that both the SCID-hu retinal and SCID-hu thy/liv implant models are useful for determining in vivo activity against HCMV, and appear to be predictive of efficacy for both ocular and systemic infections in humans.