Fig 2.

HCMV efficiently replicates in human fetal lung tissue implanted into CB17-scid mice. (A) Lung implants (cohort A; 24 mice) were inoculated with 6.1 log₁₀ IU of VR1814 per implant (arrow). Mice were euthanized for tissue collection, and virus titers (IU/implant) were determined at days 1, 7, and 14 after inoculation. The HCMV titer increased significantly from day 1 to days 7 and 14 (P < 0.05 by Mann-Whitney U test). (B) HCMV DNA in a lung implant from cohort A was quantified by real-time PCR. The HCMV genome number in the virus inoculum was 8.8 log₁₀ copies per implant. The numbers of HCMV DNA copies/implant at 14 days were significantly higher than those at day 1 (P < 0.05 by Mann-Whitney U test). (C) The relationship between infectious units and HCMV DNA in implants from cohort A was significant by the Spearman rank correlation coefficient (r² = 0.87; P = 0.0008). (D) Lung implants (cohort B; 15 mice) were inoculated with 5.7 log₁₀ IU of VR1814 per implant (arrow), and virus titers were determined at days 1, 7, and 14 after inoculation. (E) Lung implants (cohort E; 20 mice) were inoculated with 2.8 and 5.8 log₁₀ IU of VR1814 per implant, and virus titers were determined 14 days after inoculation. The HCMV titer was significantly higher with higher virus inocula (P < 0.05 by Mann-Whitney U test). (F) Kinetics of HCMV replication in lung implants (cohort E; 20 mice) inoculated with 2.8 log₁₀ IU (dotted lines) and 5.8 log₁₀ IU (solid lines). (G) Lung implants (cohort C; 14 mice) were inoculated with 5.4 log₁₀ IU of VR1814 per implant (arrow), and mice were treated intraperitoneally once daily with ganciclovir beginning the day before HCMV inoculation. Compared to untreated mice, ganciclovir treatment significantly decreased lung virus titers (P < 0.001 by Mann-Whitney U test). (H) Lung implants (cohort D; 40 mice) were inoculated with 5.8 log₁₀ IU of VR1814 per implant (arrow), and mice were treated orally twice daily with valganciclovir beginning the day before inoculation. Compared to untreated mice, valganciclovir treatment significantly decreased the titer of virus at doses of 100 and 300 mg/kg/day (P < 0.05 [by Mann-Whitney U test]). The bar represents the median value. The dotted line is the limit of detection for HCMV IU (1 log₁₀ IU/implant) (A and D to H) or HCMV DNA (1 log₁₀ HCMV copies/implant) (B).