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Interactions with cellular stress pathways are central to the life cycle of many latent viruses. Here, we utilize adeno-associated virus (AAV) as a model to study these interactions, as previous studies have demonstrated that cellular stressors frequently increase transduction of recombinant AAV (rAAV) vectors and may even substitute for helper virus functions. Since several chemotherapeutic drugs are known to increase rAAV transduction, we investigated the effect of arsenic trioxide (As2 O3 ), an FDA-approved chemotherapeutic agent with known effects on several other virus life cycles, on the transduction of rAAV.In vitro , As2 O3 caused a dose-dependent increase in rAAV2 transduction over a broad range of cell lines from various cell types and species (e.g., HEK-293, HeLa, HFF hTERT, C-12, and Cos-1). Mechanistically, As2 O3 treatment acted to prevent loss of virions from the perinuclear region, which correlated with increased cellular vector genome retention, and was distinguishable from proteasome inhibition. To extend our investigation of the cellular mechanism, we inhibited reactive oxygen species formation and determined that the As2 O3 -mediated increase in rAAV2 transduction was dependent upon production of reactive oxygen species. To further validate ourin vitro data, we tested the effect of As2 O3 on rAAV transductionin vivo and determined that treatment initiated transgene expression as early as 2 days posttransduction and increased reporter expression by up to 10-fold. Moreover, the transduction of several other serotypes of rAAV was also enhancedin vivo , suggesting that As2 O3 affects a pathway used by several AAV serotypes. In summary, our data support a model wherein As2 O3 increases rAAV transduction bothin vitro andin vivo and maintains perinuclear accumulations of capsids, facilitating productive nuclear trafficking.

journal of virology

Arsenic Trioxide Stabilizes Accumulations of Adeno-Associated Virus Virions at the Perinuclear Region, Increasing Transduction <i>In Vitro</i> and <i>In Vivo</i>

Arsenic Trioxide Stabilizes Accumulations of Adeno-Associated Virus Virions at the Perinuclear Region, Increasing Transduction In Vitro and In Vivo