Herpes simplex virus (HSV) and herpes (varicella) zoster virus (VZV) are two of the most common ailments afflicting mankind. Most often they induce mild mucocutaneous infection which readily lends itself to rapid and accurate viral diagnosis. By contrast, life-and target organ-threatening infections with these viruses often evade diagnosis, because of difficult access to infected tissues. Recent advances in chemotherapy of HSV and VZV infections have resulted in an expansion of the need to eliminate invasive testing, along with its inherent inaccuracies, delays, morbidity, and controversy. Several groups have suggested the possibility of using radiolabelled nucleosides which depend upon herpes-specified deoxythymidine kinases (dTK's) for phosphorylation. Samuel, et al, have used E-5-(2- [131I]iodovinyl)-2'-deoxyuridine (131IVdU). Unfortunately, because of the rapid metabolic breakdown of this compound to the nonspecific metabolite, iodovinyl uracil (IVU), a high background problem resulted. To correct for this, a nucleoside with minimal catabolism in vivo should be used. Ideally, a radiolabelled antiviral nucleoside for noninvasive diagnosis should make use of a clinically proven radioisotope, which lends itself to a widely available, and highly specific labelling process. Minimizing passive uptake into uninfected tissue, while maximizing uptake and phosphorylation in infected tissue will also be required. In collaboration with Dr. Morris Robbins, a synthetic chemist, a novel radiolabelled nucleoside, 1-beta-D-arabinofuranosyl-E-5-(2-[125I]iodovinyl) uracil (125IVaraU) has been designed. IVaraU in its cold form, does not readily pass into cells not expressing viral dTK, yet large quantities are present in HSV-infected cells, which can be detected using high performance liquid chromatography. Unlike IVdU, IVaraU is not cleaved to IVU, thereby obviating the problem of background uptake. In order to study the potential for clinical use of this compound as a noninvasive diagnostic agent, a rabbit model of HSE with a focal, hemorrhagic process, akin to human disease was developed. It is now planned to study the nature of, as well as the sensitivity and specificity of 125I and 123I-VaraU uptake in this animal model as a function of viral titer and disease severity. The specificity of uptake as well as the reversibility of uptake after discontinuation of exposure to the radiolabel will also be assessed. In addition, the potential for use of this compound as an in vitro diagnostic tool will be examined. A successful outcome to these studies will directly enhance the physician's ability to diagnose serious herpesvirus infections, by increasing the rapidity of diagnosis as well as the accuracy and safety of the test.
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