AAV vs. Lentiviral Vectors: When to Use Which

Two workhorse systems with different strengths

In gene and cell therapy, Adeno-Associated Viral vector (AAV) and Lentiviral Vector (LVV) are the two most widely used delivery platforms.

Both have advanced from research to the clinic (and beyond), but each brings unique strengths - and tradeoffs. Understanding when to use AAV vs. LVV is critical for matching the right tool to the right therapeutic problem.

AAV at a Glance

Key Features

  • Non-integrating (remains mostly episomal, unless delivered in combination with CRISPR/Cas gene editing tools)

  • Can target a range of tissues depending on serotype…and the serotype can be engineered

  • Packaging capacity: ~4.7 kb genome

Strengths:

  • Strong track record with gene therapies (think: Luxturna)

  • Low risk of insertional mutagenesis

Limitations:

  • Small payload size (especially limiting when you want to deliver >1 gene)

  • Pre-existing immunity in many patients

  • May require re-dosing, which can be complicated by immune response

Lentiviral Vectors at a Glance

Key Features:

  • Derived from HIV-1, but replication-incompetent and engineered for safety

  • Genome integrates at random sites into host DNA

  • Packaging capacity: ~8-10 kb genome

Strengths:

  • Proven to be very efficient for ex vivo modification of cells (e.g. CAR-T therapy)

  • Larger payload capacity than AAV

  • Stable, long-term expression once integrated

Limitations:

  • Integration raises safety considerations (though modern designs mitigate risks)

  • Manufacturing can be more complex and costly

Side-by-Side Comparison Table

When to Use Which

Choose AAV if:

  • You need to deliver a small gene directly to patient tissue (in vivo)

  • Long-term expression without integration is acceptable…

  • …Or you intend to do gene editing (in combination with CRISPR/Cas)

Choose LVV if:

  • You’re modifying cells ex vivo and you want a system that’s plug-and-play (…or at least as much as you can get in cell & gene therapy)

  • You need to deliver larger or more complex genes

  • Stable integration is necessary, but the specific site of integration doesn’t matter (i.e. you don’t need targeted gene knock-out)

Key Takeaways

  • Both AAV and LVV are clinically validated and powerful - but serve slightly different roles

  • AAV currently dominates in vivo therapies, whereas LVV leads with ex vivo (though that landscape is changing)

  • Careful consideration of payload size, target cells, and clinical context helps to drive the choice

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