Personalized gene therapy helps fight HIV infection
Researchers at the University of Pennsylvania, working under the guidance of Professor Carl H. June, with the help of genetic modification, "taught" the immune cells of HIV-positive patients to resist infection. As a result, the majority of patients had a significant decrease in viral load, despite the fact that half of them had been canceled antiretroviral therapy. At the same time, in one of the patients, the viral load decreased to unregistered values.
The authors used the technology of "zinc fingers" to modify patients' T-lymphocytes according to the principle of "molecular scissors". This allowed them to recreate the CCR5-delta-32 mutation in the DNA of cells. This rare mutation provides natural resistance to HIV, but occurs only in 1% of people. It is manifested by a decrease in the number of CCR5 protein molecules expressed on the surface of T-lymphocytes, in the absence of which HIV cannot penetrate into cells.
A total of 12 HIV-infected patients participated in the phase I clinical trial. Approximately 10 billion modified cells, called SB-728-T. 11-28% of these cells had an artificially created CCR5-delta-32 mutation, were injected into each of them once between May 2009 and July 2012. Half of the patients 4 weeks after the procedure, antiretroviral therapy was completely discontinued for 12 weeks, while the second half of the patients continued to adhere to the standard treatment protocol.
Subsequent monitoring of the patients' condition demonstrated the safety and tolerability of injections. A week after the procedure, patients experienced a multiple increase in the number of modified T cells in the body. Despite the fact that the number of modified T-lymphocytes in the bloodstream gradually decreased over time, upon discontinuation of antiretroviral therapy, it was less pronounced than the decrease in the number of unmodified cells. Modified cells were also detected in intestinal-associated lymphoid tissue, which is a major depot of immune cells and an important reservoir of HIV infection. This indicates the normal functioning and movement of modified cells in the body.
The results of the examination of patients also demonstrated the effectiveness of suppressing HIV activity using an experimental approach. Almost all participants, including 4 patients from the group with interrupted antiretroviral therapy, had a decrease in viral load. In one of the latter, the viral load fell below the detection limit. Interestingly, a heterozygous CCR5-delta-32 mutation was subsequently detected in this patient.
Therapies based on the CCR5 gene mutation have gained popularity over the past six years, especially after the reported case of the so-called "Berlin patient". This HIV-infected man was "functionally" cured of HIV in 2008 as a result of hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia. His donor is homozygous for the CCR5 gene mutation, that is, it has it in two alleles of the gene inherited from both parents.
Researchers are trying to reproduce this phenomenon in other ways, since allogeneic bone marrow transplantation is associated with a high risk of mortality and requires prolonged hospitalization. Its implementation is impractical for HIV-infected patients who do not have oncological diseases of the circulatory system. In addition, donor cells must have a CCR5 mutation in two alleles, which is very rare. This was confirmed in a recent clinical study involving two "Boston patients" who underwent transplantation of donor stem cells having one copy of the desired mutation. After a short period of functional remission, the viral load in their blood increased dramatically.
In the near future, the authors plan to conduct new studies aimed at analyzing the dynamics of the content of modified T-lymphocytes in larger cohorts of patients, as well as developing strategies to increase the number of virus-resistant cells in the blood, which will achieve a more pronounced therapeutic effect.
Article by Pablo Tebas et al. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV is published in the New England Journal of Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Pennsylvania:
Personalized Gene Therapy Locks Out HIV, Paving the Way to Control Virus Without Antiretroviral Drugs.
11.03.2014