Researchers have, for the first time, cut a segment of HIV genetic material (Deoxy ribonucleic Acid/DNA) from the genes of living animals.
The discovery published in the journal Gene Therapy marks an exciting step on the road to eradicating the virus. They have hailed the breakthrough ‘critical’ in the development of a potential cure for HIV.
Also, scientists have provided an explanation why a small number of patients infected by HIV spontaneously control the replication of the virus, without the need for antiretroviral drugs. As a result, they do not go on to develop the disease.
The ability of these rare patients, known as ‘HIV controllers’, to suppress HIV replication appears to be down to a highly effective immune system.
Now, a team of scientists at the Institut Pasteur in Paris and Inserm, France’s national institute of health and medical research have in a study published in the Journal of Clinical Investigation identified what it is that stimulates such an effective immune response.They believe that CD4+ T-immune cells (markers of the immune system) in these patients are capable of recognising tiny quantities of the virus.
This highly sensitive detection is dependent on the expression of specific T-cell receptors on the surface of the CD4+ immune cells, which target the HIV protein with high affinity.
The preferential expression of these receptors appears to keep the immune system on a constant state of alert, thereby enabling the patients’ bodies to control HIV.
Meanwhile, Prof. Kamel Khalili who led the study at Temple University, published in Gene Therapy, said: “In a proof-of-concept study, we show that our gene-editing technology can be effectively delivered to many organs of two small animal models and excise large fragments of viral DNA from the host cell genome.” Current treatment for HIV infection is centered on the use of a combination of antiretroviral drugs.
While antiretroviral (ARV) drug therapy can effectively suppress HIV replication, it has no ability to eliminate HIV-1 – the AIDS-causing virus – from infected cells.
Moreover, when antiretroviral therapy is interrupted, HIV replication rebounds, placing patients at risk for developing acquired immune deficiency syndrome, or AIDS.
These latent infections occur because HIV DNA is able to persist in CD4+ T-cells – a type of white blood cell that protects the body from infection.
It is also thought the virus can hide in other reservoirs in the body, where it remains inactive and out of sight of current drug treatments.
In their past research, Khalili, showed their novel gene-editing system, which is based on CRISPR technology, has the ability to eliminate HIV-1 from infected cells in vitro, with no adverse effect on the host cells.Furthermore, ex vivo experiments showed viral replication was significantly reduced following treatment with the gene-editing system.
The new study aimed to specifically test whether gene-editing technology could also eliminate HIV-1 in rats and mice, where every cell and organ had been infected with HIV DNA.
Researchers then delivered the gene-editing technology into the living animals, via a recombinant adeno-associated viral vector (rAAV) system. Two weeks after introducing these molecules into the animals’ bloodstream, the researchers analysed the DNA of tissue samples.
The results showed that the targeted segment of HIV-1 DNA had been ‘cut out’ from the viral genome in every tissue, including the brain, heart, kidney, liver, lungs, spleen and blood cells.
They found, in rats, the strategy significantly reduced levels of HIV-1 Ribo Nucleic Acid (RNA) in lymphocytes – a type of white blood cell – as well as lymph nodes.
Meanwhile, the French researchers led by Lisa Chakrabarti of the Institut Pasteur and Inserm, in collaboration with Olivier Lambotte from Bicêtre Hospital, France, in the research published in the Journal of Clinical Investigation noted: “‘HIV controller’ patients represent less than 0.5 per cent of all HIV-infected people.”
They are proof that in some cases the human immune system can resist the harmful effects of HIV.These patients’ bodies are able to maintain a population of CD4+ T lymphocyte cells.In patients that have gone on to develop the disease these cells are destroyed or rendered inactive by the infection.
In order to arrive at their findings, researchers examined a group of patients living in France.To trigger the antiviral immune response, the CD4+ T-cells in ‘HIV controllers’ are able to produce numerous cytonkines – cell signalling molecules – in response to very low doses of HIV antigens.
Scientists discovered that these highly sensitive responses were due to the expression of particular T-cell receptors (known as TCRs) on the surface of the ‘HIV controllers’ CD4+ T-cells.
In contrast, these T-cell receptors were rarely found on the CD4+ T-cells of patients receiving treatment.Scientists hope in future immune-therapy treatments will be able to transfer or boost these key T-cell receptors, to help restore effective antiviral responses in patients who have gone on to develop HIV.
In the meantime, the next step is to conduct a follow-up study in a larger group of animals, in which the researchers plan to monitor for effects of the treatment, its safety, and other important indices.
By: Chukwuma Muanya
The Guardian News