Table 3.

Viral vector genomic integration and insertional mutagenesis risk

Virus Type	Genomic Integration and Transformation Risk	References
Gammaretrovirus	Insertional oncogenesis observed with ex vivo retrovirally mediated gene transfer, using Moloney murine leukemia virus, of the interleukin-2 receptor γ-chain gene into CD34+ cells in patients with severe combined immunodeficiency. Insertional mutagenesis involving LMO2 and identified the potential involvement of other proto-oncogenes, including CCND2 and BMI1. Genomic integration bias in and near gene coding regions and around transcription start sites.	13, Table 1—Guidance P, X
Lentivirus	HIV-associated cancer risk is attributed to reduced cancer immune surveillance and not to virally mediated insertional oncogenesis. Integration biased to active transcription regions and genomic regions enriched in G/C bases, near transcription-associated histone modifications, and genomic regions structurally associated with outward-facing DNA major grooves. A consensus nucleotide-enrichment pattern around the integration sites has been established.	20,23–25
AAV	Generally considered an episomal virus, although viral integration occurs at a low frequency (∼0.1–0.5% integrations per AAV infectious unit) and is generally random. Because rAAV vectors are deficient in the Rep gene, they lack the targeted integration capacity of wt AAV, which typically integrates in chromosome 19, at actively transcribed genomic regions and regions associated with DNA breaks. DNA breaks from CRISPR/Cas gene editing also provides sites for AAV integration.	31, Table 1—Guidance B, AC

Cas, CRISPR-associated; CRISPR, clustered regularly interspaced short palindromic repeats; rAAV, recombinant AAV; wt, wild type.