Mapping theIn VivoDistribution of Herpes Simplex Virions

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Abstract
We describe a method for labeling enveloped viral particles with a radiotracer, indium-111, allowing labeled viruses to be traced in vivo by nuclear imaging. After initial optimization experiments, a labeling efficiency of 83% (incorporation yield) was achieved for herpes simplex virus (HSV), resulting in a specific activity of 30 μCi/109 PFU. The labeling procedure did not significantly reduce the infectivity of the labeled virus and the virus did not release any significant amounts of the radionuclide within 12 hr after labeling. Sequential imaging of animals after intravenous administration of the labeled virus showed fast accumulation in the liver and redistribution from the blood pool (immediately after injection) to liver and spleen (12–24 hr after injection). At 12 hr after injection 7% of the virus-associated 111In had been eliminated from the body and the remaining organ distribution of the virus was as follows: spleen 28.7 ± 5.4% ID/g; liver, 26.0 ± 5.1% ID/g; kidney, 9.8 ± 3.1% ID/g; lung, 5.7 ± 1.0% ID/g; and lower amounts in other organs. Our results indicate that the described method allows qualitative and quantitative assessment of viral biodistribution in vivo by nuclear imaging. We report a novel approach for noninvasive monitoring of enveloped virions, potential high-efficiency vectors for human gene therapy. A replication-deficient variant of herpes simplex virus (HSV) has been labeled with a high-energy γ emitter (111In) for the purpose of tracing the labeled virions by γ camera imaging. We established that by using a lipophilic complex of 111In with hydroxyquinoline HSV can be labeled, with isotope incorporation exceeding 80%. In labeling experiments a specific activity of 30 μCi/109 PFU could be achieved. Higher specific activities of up to 253 μCi/109 PFU could be achieved, but with lower labeling efficiency (23%). The label was stably associated with viral particles and was not removed during dialysis. Intravenously administered labeled virions showed rapid disappearance from the blood pool and accumulated predominantly in liver and spleen. Correlation of in vivo imaging and histology showed that labeled HSV was capable of transducing cells in target organs.