An siRNA-Based Microbicide Protects Mice From Lethal Herpes Simplex Virus 2 Infection
Palliser, D., Chowdhury, D., Wang, Q-Y., et al. Nature, 439, 89-94 (January 4, 2006)
Seven siRNAs were created against three essential herpes simplex virus 2 (HSV-2) genes, UL5 (a component of the helicase-primase complex), UL27 (envelope glycoprotein B), and UL29 (a DNA-binding protein). A cell culture assay was used to determine efficacy of each in suppressing viral replication, and the most effective was tested further to determine the optimal intravaginal dose for protecting against a normally lethal exposure to HSV-2 (2 x LD50). At the optimal dose of 500 pmol given 2 hours before and 4 hours after infection, UL29.2 siRNA limited the number of deaths to 25% (versus 75% in the control group), and significantly delayed the time to death. Nonetheless, 55% of the treated animals developed signs of infection. By day 11 post-infection, though, the survivors were free of clinical disease. The siRNA UL27.2, which was less effective in the cell culture assay, provided less protection in vivo.
A histological evaluation found intact mucosal epithelium with few inflammatory cells in UL29.2 siRNA treated mice, versus evidence of cell death and immune system involvement in tissue from untreated animals. Also, there was no evidence of interferon-mediated inflammation associated with the siRNA therapy, and an evaluation of virus isolated from control and UL29.2 treated mice showed no signs of escape mutation.
To test whether siRNA offers protection when administered after viral exposure, mice were infected with HSV-2 and then given UL29.2 or UL27.2 (500 pmol), or a combination of the two (250 pmol each) intravaginally at 3 and 6 hours post-infection. The separate siRNAs failed to prevent death, but the combination therapy enabled 5 of 6 mice to survive.
This study lends support to the theory that siRNAs offer a new approach to preventing viral infections. The prophylactic therapy affords protection over multiple days, which suggests that it may prove convenient to use by obviating the need for administration immediately prior to exposure. Moreover, the therapy targeting multiple viral genes appears efficacious when given shortly after infection. Based on these findings and the fact that HSV-2 poses a serious health threat alone and as a cofactor in the transmission of HIV infection, further work is warranted to evaluate siRNAs as a therapy for sexually transmitted diseases.
Message posted by: Keith Markey
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