A team of Dutch scientists has taken a significant step towards the elimination of HIV from infected cells using Crispr-Cas gene editing technology, also known as “molecular scissors”. Presented in advance at the 2024 European Congress of Clinical Microbiology and Infectious Diseases, the preliminary results demonstrate the ability to completely cleave HIV DNA from infected cells in cell cultures. This approach, which aims to develop an inclusive cure for HIV by inactivating different strains of the virus in various cellular contexts, represents a milestone in the fight against HIV. By using two guide RNAs against conserved HIV sequences, scientists were able to cure infected T cells. Despite challenges related to the size of the vectors used to deliver the Crispr-Cas tools and the need to reach HIV “reservoir” cells, the progress made is promising. The next steps will include system optimization and preclinical studies to evaluate efficacy and safety, with the ultimate goal of initiating human clinical trials to eliminate the HIV reservoir.
HIV virus, the study on “DNA cutting”
Experts point out that these are “very encouraging” preliminary results, but there is a lot of work to be done to transform this into a cure for HIV. In the meantime, however, the validity of the approach that involves “cutting” HIV DNA from infected cells is confirmed and this work, experts explain, fuels hopes of a treatment that eliminates the infection. It is a “significant step forward” in the search for this cure, it is highlighted. The studies were conducted by Elena Herrera-Carrillo and her group (composed of researchers Yuanling Bao, Zhenghao Yu and Pascal Kroon) atUniversity Medical Center di Amsterdam. Crispr-Cas gene editing technology is a method that has revolutionized molecular biology: it allows precise alterations to the genomes of living organisms. A technique that earned its inventors, Jennifer Doudna and Emmanuelle Charpentier, the 2020 Nobel Prize for Chemistry. With these molecular scissors, scientists can precisely locate and modify specific segments of an organism’s genetic code.
HIV, a study would have found a new cure using the Crispr gene
Crispr-Cas cuts DNA at precise points with the help of guide RNA (gRNA). This action facilitates the deletion of unwanted genes or the introduction of new genetic material into an organism’s cells, paving the way for advanced therapies. All this can help with one of the most complex challenges in HIV treatment. The virus is in fact capable of integrating its genome into the host’s DNA, making its elimination extremely difficult. Numerous powerful antiviral drugs are currently in use for HIV infection. Despite their effectiveness, lifelong antiviral therapy is essential, as the virus can reappear from existing reservoirs when treatment is stopped.
Crispr-Cas genome modification
The authors explain that the Crispr-Cas genome editing tool provides a new means to target HIV DNA. “Our goal – they explain – is to develop a robust and safe regime, seeking an all-inclusive ‘HIV cure’ that can inactivate different HIV strains in various cellular contexts.” The virus can infect different types of cells and tissues in the body, each with its own unique environment and characteristics. Researchers are therefore looking for a way to target HIV in all these situations. The research used the Crispr-Cas molecular scissors and two guide RNAs (gRNAs) against the “conserved” sequences of HIV, in practice the focus was on parts of the virus genome that remain the same in all known strains. By doing so, scientists have obtained a cure for HIV-infected T cells.
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By focusing on these conserved sections, the approach aims to provide a broad-spectrum therapy capable of effectively combating multiple variants of HIV. However, there are some challenges to overcome: first of all the logistical challenge represented by the too large dimensions of the carrier used to transport the “toolbox” that encodes the Crispr-Cas therapeutic reagents into cells. Researchers have experimented with various techniques to reduce their size and are now attempting to load the large “luggage” into a “compact car” for the journey to the infected cell, and are looking for ways to downsize the “luggage” in question for easier transportation. Another problem is reaching the HIV “reservoir” cells that experience a rebound effect when HIV antiretroviral treatment is stopped.
The combined attack on the HIV virus
The authors evaluated various Crispr-Cas systems to understand their efficacy and safety in the treatment of HIV-infected Cd4+ T cells. And they shared results on two of these systems. In particular, SaCas9 showed significant antiviral performance, managing to completely inactivate HIV and remove viral DNA. The strategy of minimizing the size of the vector was successful, improving “delivery” to infected cells. And scientists were able to target the hidden reservoirs of the virus. «We have developed an efficient combined attack on the HIV virus and demonstrated that therapies can be administered specifically to the cells of interest. It is progress towards designing a treatment strategy.” A cure that will not arrive immediately, they reiterate: «Our next steps involve the optimization» of various aspects and the transition «to preclinical models to study efficacy and safety in detail». The researchers then underline the mission of the study: «To avoid the release of Crispr-Cas in non-reservoir cells and make the system as safe as possible for future clinical applications». Once the right balance has been achieved, “we will be able to consider clinical ‘cure’ trials in humans to deactivate the HIV reservoir.”
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