Researchers have determined the optimal number of stem cells needed for HIV treatment

American scientists reported that they were able to identify the optimal conditions for stem cell transplantation, which could control HIV, without the need for daily pills. The right balance between stem cell dose and duration of antiretroviral therapy (ART) can lead to spontaneous HIV cure.

To date, only two cases of HIV cure are known: the Berlin Patient and the London Patient. Both of them underwent transplantation of donor stem cells (SC), which lacked the CCR5 gene responsible for interaction with HIV.

“The major obstacle to HIV eradication is a latent reservoir of long-lived infected cells, and cure strategies aim to eliminate all infected cells or permanently prevent viral reactivation from latency”, – explains first author E. Fabian Cardozo-Ojeda, Senior Staff Scientist at the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, US. “We wanted to recreate the cures seen in the Berlin and London patients but with reduced toxicity.”

In their new study, the results of which were published in eLife, the team sought to improve existing treatments, which include obtaining bone marrow stem cells from the patient, removing the CCR5 gene, and then transplanting SC back into the patient. This technology is undergoing early clinical trials in people with HIV.

However, the minimum dose of genetically engineered stem cells required for long-term remission or cure, demonstrated in the case of patients from Berlin and London, is still unknown.

To solve this problem, the researchers developed a multi-step mathematical model to study the dynamics of changes in the level of residual and transplanted stem cells, HIV viral load (the quantity of virus in the blood), and how they are affected by time withdrawal of ART. The model is based on previously obtained data on 22 monkeys with monkey immunodeficiency virus, which were transplanted stem cells with or without CCR5 gene editing. A year later, antiretroviral therapy was discontinued in some animals.

The dynamics of immune cells and viral load in different animals differed, but the common thing was that the viral load after the withdrawal of ART was higher in animals that underwent SC transplantation compared with those who did not receive treatment. This suggests that stem cell transplantation may decrease the immune system’s response to HIV. The team suggested that immunity could be restored by removing the CCR5 gene from the transplanted stem cells.

To support this theory, scientists have created a model to analyze the conditions required to achieve control of the virus after ART withdrawal. They found two important conditions: first, the dose of stem cells to be transplanted must be at least five times the number of residual stem cells. Secondly, the number of stem cells with the edited CCR5 gene should be at least 76-94% of the total population of transplanted stem cells.

“Our model predicts that viral control is possible after transplantation of autologous stem cells with edited genes if enough genetically modified stem cells circulate in the blood before stopping ART”, – concludes senior author Joshua T. Schiffer. Associate Professor, Department of Vaccines and Infectious Diseases, Cancer Research Center. Fred Hutchinson. “The results demonstrate the power of mathematical models to optimize HIV treatment strategies.”