Gene editing with CRISPR/Cas9 may not be the safest HIV cure strategy.

[Jim Allen]

Aidsmap article in full: https://www.aidsmap.com/news/nov-2023/gene-editing-may-not-be-safest-hiv-cure-strategy-early-findings-warn

Spanish forum thread on this topic: https://forums.poz.com/index.php?topic=77541

In Brief:

Gene editing with CRISPR/Cas9 can lead to unwanted ‘cuts’ and changes in the gene sequences near to the integrated HIV genes, Dutch researchers report in the Journal of Virology. This might activate host genes that could contribute to cancer development, raising concerns about this potential HIV cure strategy.

The Dutch microbiologists used different kinds of HIV-infected cell types in a laboratory to test whether the gene editing machinery was accurate enough to target only the HIV provirus sequences amidst an ocean of human DNA and whether the ‘cutting’ part was precise enough to not damage nearby DNA sequences of the cell.

They found that the editing machinery was precise in finding the target (the provirus sequences). But the cutting part led to the random removal or addition of DNA sequences in the neighbouring non-viral regions surrounding the proviral sequence. This would directly translate into changes in the DNA of the person being treated with gene editing.

Using additional laboratory approaches, they were also able to establish the source of these unwanted DNA changes. It turned out that it was not the ‘editing machinery’ that was directly changing and damaging these neighbouring DNA sequences, but the DNA repair process of the cells itself.

The editing machinery leads to the formation of a cut in both strands of the DNA molecule in order to introduce the damaged sequences into the target (the proviral sequence). A double-strand break is one of the strongest alarm bells in a cell for danger and the cell has many mechanisms in place to quickly correct the break and join both ends of the double-stranded DNA molecule. Some of the mechanisms are very efficient and lead to a complete and very accurate repair, while others can compromise the accuracy of the repair

Concluding thoughts

Gene editing using CRISPR/Cas9 is relatively new and both its efficacy and its risks are yet to be fully explored. The findings from this study show that the editing machinery is precise in finding its target, but the DNA repair process following the editing seems to be inefficient. This may lead to changes in our DNA (mutations) that can potentially increase the risk of diseases, particularly cancer later in life.

However, we have to bear in mind that these findings are from cell cultures outside the body which may not tell us the complete story. In one way, these effects could be even more dramatic as our bodies have hundreds of thousands of times more cells, hence more error-making potential. However, in a system, cells often behave differently compared to a lab dish, so they may be more efficient in DNA repair.

Besides, it is known that some viral infections including HIV increase the risk of cancers themselves, so it's possible that the risk of cancer would be greater if HIV was left uncured.

Liu Y. et al. CRISPR-Cas attack of HIV-1 proviral DNA can cause unintended deletion of surrounding cellular DNA. Journal of Virology, online ahead of print, 20 November 2023. DOI: https://doi.org/10.1128/jvi.01334-23