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Using the modified CRISPR-Cas9 gene editing system and a therapeutic strategy known as slow-acting and long-acting antiviral therapy (LASER ART), a team of researchers eliminated the DNA of the HIV-1 competent for the replication of living mouse genomes. Posted in the journal Nature Communications, the study marks a crucial step in the development of a cure for HIV infection in humans.
Scanning electron micrograph of HIV particles infecting a human T lymphocyte. Image credit: National Institutes of Health.
"Our study shows that a treatment aimed at suppressing HIV replication and gene modification therapy, when administered sequentially, can eliminate HIV from animal cells and organs." infected, "said Professor Kamel Khalili, of the Lewis Katz School of Medicine at Temple University.
Current treatment against HIV is focused on the use of antiretroviral therapy (ART), which inhibits HIV replication but does not eliminate the body's virus.
Therefore, therapy is not a cure for HIV, it requires a lifetime use. When it is stopped, HIV bounces, renewing replication and fueling the development of AIDS.
The rebound of HIV is directly attributed to the ability of the virus to integrate its DNA sequence into the genomes of immune system cells, where it is dormant and out of reach of antiretroviral drugs.
In previous work, Professor Khalili and his colleagues used CRISPR-Cas9 to develop a new gene therapy editing and therapy system to remove HIV DNA from genomes harboring the virus.
In rats and mice, they showed that the gene editing system, dubbed AAV9-CRISPR-Cas9, could actually excise large fragments of HIV DNA from infected cells, which would have a significant impact on viral gene expression. Similar to antiretroviral therapy, gene editing can not, however, completely eliminate HIV.
A working model for the elimination of HIV-1: a cartoon illustration of the strategy of elimination of the virus is presented for ART LASER, AAV9-CRISPR-Cas9 single injection groups and the double treatment groups. Image credit: Dash et al, doi: 10.1038 / s41467-019-10366-y.
For this new study, researchers have combined their gene editing system with LASER laser therapy, which targets viral sanctuaries and keeps HIV replication at low levels for long periods of time, reducing the frequency of administration. TAR.
Long-term drugs have been made possible by pharmacological changes in the chemical structure of antiretroviral drugs. The modified drug has been packaged in nanocrystals, which are easily distributed in tissues where HIV is likely to be dormant. From there, the nanocrystals, stored in cells for weeks, slowly release the drug.
"We wanted to see if the laser treatment could suppress HIV replication long enough for CRISPR-Cas9 to completely rid the cells of viral DNA," said Professor Khalili.
To test their idea, Professor Khalili and his co-authors used mice designed to produce human T cells sensitive to HIV infection, thus enabling long-term viral infection and ART-induced latency. .
Once the infection was established, the mice were treated with LASER ART and then with CRISPR-Cas9.
At the end of the treatment period, the mice were examined for viral load.
The analyzes revealed complete elimination of HIV DNA in about one-third of HIV-infected mice.
"The big message of this work is that it takes both CRISPR-Cas9 and the removal of the virus through a method such as the ART LASER, administered jointly, to help cure the disease." HIV infection, "said Professor Khalili.
"We now have a clear path to go forward with trials on nonhuman primates and possibly clinical trials on human patients a year from now."
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Prasanta K. Dash et al. 2019. Sequential LASER treatments and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice. Nature Communications 10, article number 2753; doi: 10.1038 / s41467-019-10366-y
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