Cellular transduction mechanisms of adeno-associated viral vectors

•AAV exploits a spectrum of endocytic pathways after cellular uptake.•AAV trafficking through the trans-Golgi network precedes nuclear entry.•Second-strand synthesis is a rate limiting step in AAV transduction.•Strategies to circumvent AAV interactions with host restriction factors can help augment transduction.

Recombinant adeno-associated viral vectors (rAAV) are regarded as promising vehicles for therapeutic gene delivery. Continued development and new strategies are essential to improve the potency of AAV vectors and reduce the effective dose needed for clinical efficacy. In this regard, many studies have focused on understanding the cellular transduction mechanisms of rAAV, often with the goal of exploiting this knowledge to increase gene transfer efficiency. Here, we provide an overview of our evolving understanding of rAAV cellular trafficking pathways through the host cell, beginning with cellular entry and ending with transcription of the vector genome. Strategies to exploit this information for improving rAAV transduction are discussed.