HIV develops resistance from CRISPR genome editing

HIV develops resistance from CRISPR genome editing

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It appears that the HIV can quickly develop resistance from CRISPR genome editing. A recent study by researchers Chen Liang et al reported that CRISPR/Cas9-derived mutations do not only inhibit the replication of HIV-1 but also accelerate viral escape.

Several studies have earlier demonstrated the potential of CRISPR/Cas9 genome editing to cure HIV infection. By programming the CRISPR/Cas9 enzyme to target a specific DNA sequence, the genome editing tool can excise viral DNA from the infected cell, thus rendering the virus unable to replicate or completely removed.

Take note that the human immunodeficiency virus highjacks the DNA-replicating machinery of an immune cell or T cell by inserting its own genome. The infected cell essentially becomes a factory for HIV replication. The CRISPR/Cas9 genome editing system equips the host cell with an enzyme that could find and cut the HIV genome.

But the study of Liang et al found that the infected T cells equipped with the CRISPR/Cas9 system were pumping out copies of virus particles that had escaped the genome editing attack. A DNA analysis revealed that the virusdeveloped mutations near a particular CRISPR/Cas9-targeted DNA sequence. In other words, HIV has developed resistance from CRISPR genome editing

Another earlier study by Das et al also reported similar findings. In sequencing the new HIV variant, they found out that although the CRISPR/Cas9 system inhibited virus replication, the new HIV-1 variant revealed nucleotide insertions, deletions, and substitutions around the Cas9/gRNA cleavage site that are typical for DNA repair by the nonhomologous end-joining pathway.

In a way, the mutation or resistance from CRISPR genome editing was not really surprising. HIV is a persistent retrovirus. It already demonstrated ability to evolve resistance from antiretroviral drugs. One of the reasons why HIV can quickly develop resistance is the rate at which it replicates. The virus can produce billions of copies a day and this high turnover results in errors or mutations. Some mutations could lead to the development of resistance.

But the discovered HIV resistance from CRISPR genome editing has a slightly different mechanism. The separate studies of Liang et al and Das et al explained that excising portion of the HIV DNA from the host cell using the CRISPR/Cas9 system triggers a natural cell repair process called nonhomologous end joining or NHEJ repair. This process is susceptible to errors that result in insertion and deletion mutations, or indels. Some of these mutations were minor enough that the virus was able to escape and infect other cells.

Simply put, the CRISPR/Cas9 system directly and immediately induces mutation that both inhibits the replication of HIV-1 while also facilitating DNA repair that leads to an accelerated viral escape. The mutated left the CRISPR/Cas9 system unable to recognize the targeted viral DNA, thus leaving the virus immune to future CRISPR attack.

The newly discovered HIV resistance from CRISPR genome editing does not completely shun off the potential of CRISPR-based HIV treatment. Liang et al suggested that one potential solution might involve simultaneously targeting two or multiple sites in the viral genome with an array of sgRNAs in the way that multiple siRNAs have been used to durably suppress HIV-1 replication. Das et al suggested the targeting of cellular genes that are essential for HIV-1 replication, such as the genes encoding the CCR5 coreceptor. They also suggested the use of CRISPR/Cas9 system alongside other antiviral approaches, either regular antiretroviral drug therapy or gene therapy strategies.

Further details of the study of Liang et al are in the article “CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape” published in April 2016 in the journal Cell Reports. Further details of the study of Das et al are in the article “CRISPR-Cas9 Can Inhibit HIV-1 Replication but NHEJ Repair Facilitates Virus Escape” published in February 2016 in the journal Molecular Therapy.

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