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Doctors newspaper online, 02.07.2019
With Genscher
US scientists have developed a method that successfully eliminates the HI virus – at least in animal experiments – and even removes it from the genome.
By Peter Leiner
3D illustration of a HI virus.
© Artem_Egorov / Getty Images / iStock
OMAHA. The retrovirus HIV is indeed able to incorporate into the genome of infected cells and thus not be vulnerable to antiretroviral drugs. For this reason, treatment of people infected with HIV has so far only succeeded in reducing the amount of virus below the detection limit, but not in extracting and destroying the pathogen from its hiding place in the genome in which it incorporates the enzyme integrase.
But only when such latent Aids pathogens are eliminated, a cure of HIV-infected people is possible. As long as this does not succeed, a lifelong drug treatment is inevitable.
On a good path to more successful HIV therapy, US researchers are now around Dr. Prasanta K. Dash of the University of Nebraska Medical Center in Omaha, Nebraska ( Nature Communications 2019; online July 2 ). They have developed a strategy in which two approaches are combined and successfully tested in animal experiments on mice.
Two Methods Combined
First, they developed a special antiretroviral therapy (ART), which they call LASER ART (long-acting slow effective release ART). The hallmark of this form of therapy is that the drugs used – dolutegravir, lamivudine (3TC) and abacavir – were packaged in nanocrystals and administered as prodrugs, released more slowly than normal and have better bioavailability.
Due to this galenic approach, researchers are ultimately supported by the activity of macrophages, which ingest these drugs and relay them via cell-cell contacts to infected CD4-positive T lymphocytes.
However, the LASER ART alone does not succeed in removing latent HI viruses that have taken root in the genetic material of cells in the preferred niches of the brain, lymph nodes, liver, bone marrow and spleen. That's why Dash and his colleagues decided to combine the special ART with the Genetic Engineering Tool CRISPR / Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat).
They used adeno-associated viruses to transport the once-only gene scissors. The strategy was tested in mice equipped with human hematopoietic stem cells from birth. These mice develop human T lymphocytes that are easily infected with HIV.
40 mice as test objects
The new strategy was tested on a total of 40 mice. The animals were first treated with LASER ART for four weeks. Thereafter, the medicines were discontinued. In the ninth week after infection with HIV-1, the researchers finally used the gene scissors and checked the tissue for HI viruses at the 14th week.
The gene scissors removed the region in the genome of HIV, which contains the gene gag (group-specific antigen), which is essential for the assembly of an infectious virus.
The researchers report that they have successfully eliminated the pathogen in more than 30 percent of infected animals using their novel strategy. Drug pretreatment enabled very efficient removal of large parts of the viral genome from infected cells using CRISPR / Cas9.
Pretreatment is a prerequisite for the successful and optimal use of the gene scissors. This had according to their statements, the cuts only in the selected places set. Accordingly, no new mutations have occurred.
Dash and his colleagues hope to soon be able to make experiments with primates and possibly their strategy for the first time in HIV patients this year to check. Her animal experiment is an important first step "on the long journey to virus eradication".
Combination of two strategies
- LASER ART is a proprietary antiretroviral therapy in which the drugs are administered as prodrugs.
- CRISPR / Cas9 is a gene scissors that has specific implications Can cut out regions in the genetic material. In the study, the researchers thus removed the gene sequence of the HI virus, in which the gag gene lies.
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