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Christian Clement, Vaibhav Tiwari, Alberto Musto, Walter J. Lukiw, Partha S. Bhattacharjee, Harris E. McFerrin, Jr., Hilary W. Thompson, James M. Hill; Neuroinvasiveness of HSV-1 High and Low Phenotypic Reactivators in Aged Infected Human Knock-in Homozygous ApoE4 Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5797.
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HSV-1 DNA deposition in neuronal tissues, ocular infectious virus shedding, and corneal damage were evaluated in 16-mo-old human homozygous ApoE (4/4 or 2/2) transgenic C57BL/6 mice infected with 17Syn+ (high) or its LAT-promoter-deletion-recombinant 17ΔPst (low) phenotypic reactivator. We have reported characteristic deposition of viral DNA in brain tissue of 5- to 8-mo-old mice (35th IHW 2010, Salt Lake City UT).
Corneas were heavily scarified and inoculated with 104 PFU/eye after each female mouse was immunized intraperitoneally with human serum (0.5 ml). A minimum of 20 transgenic and 10 parent non-transgenic mice were infected with 17Syn+ or 17ΔPst(LAT-). Eyes were swabbed daily beginning 1 day post infection (PI) and continuing for 30 consecutive days and then weekly for 6 mos. PFU in the swabs were determined by standard procedures and HSV-1 DNA copy numbers quantified. Viral DNA in TG and brain regions were quantified.
Each ApoE (4/4) mouse shed 17Syn+ or 17ΔPst(LAT-) up to 14 days PI and more than once thereafter, and all had visible keratitis. Control ApoE (2/2) shed infrequently for 1 week and there was no detectable virus in the parent C57BL/6. Daily HSV-1 DNA recovery frequency averaged 2x102 (controls, 2x10) for 14 days PI. HSV-1 DNA copy numbers in ApoE (4/4) left brain tissues were significantly increased (hippocampus, 9x10; cortex, 1x102) compared to younger mice which were euthanized 30 days PI.
Our data suggest a novel neurotropic neuronal-connection-pathway of HSV-1 DNA deposition independent of the phenotypic nature of the virus in the presence of the human ApoE (4/4) genetic background. Keratitis, corneal damage (opacity), and neovascularization in all ApoE (4/4) suggest detrimental effects of spontaneous HSV-1 shedding and possible rendering of the latency silencing to be less effective, increasing neuroinvasiveness, neurovirulence, and ocular damage.
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