Activating the immune system brake allows some children to slow the progression of HIV infection

Only 0.01% of adults with HIV infection who do not take treatment have slow disease progression. However, this control is a thousand times more common in the case of children with HIV, in which 10% reach the age of five without affecting their immune system despite having the virus present in their blood. Now, a study in which the IrsiCaixa AIDS Research Institute - a centre jointly promoted by the "la Caixa" Foundation and the Catalan Ministry of Health - and led by the University of Oxford, describes two factors that favour this control of the disease: the PD-1 molecule, which acts as a brake on the immune system, and the presence of immune cells, specifically T cells, with stem cell characteristics, a sign that the immune system is not exhausted. These data, published in the Journal of Clinical Investigation Insight, highlight the importance of these stem cell-like cells in eliminating HIV, and open up the possibility of cure strategies that enhance their function.

In general, HIV infection in the absence of treatment causes the immune system to weaken as the virus attacks one of the most important cells in our defences, the T cells. "The scientific community has seen that in children with HIV it is relatively common that this decrease in the number of T cells does not occur," explains Julia García-Prado, principal investigator at IrsiCaixa and scientific director of the Germans Trias i Pujol Research Institute (IGTP).

Slow progression in paediatric patients

To understand what mechanisms enable this initial disease control, the researchers followed 13 children in Durban, South Africa. All of them had started antiretroviral therapy for HIV within days of birth and had their treatment stopped 12 months later. During the study, the number of T-cells in their blood was monitored and, if it fell below the threshold set by the research team, the participants resumed treatment. "We detected four cases of people who progressed slowly. All four maintained high levels of immune cells and did not need to restart antiretroviral therapy for at least four years. The rest of the participants, on the other hand, had to restart treatment more quickly, most of them before 2 years," explains Miguel Marín-López, pre-doctoral researcher at IrsiCaixa.

Preventing the exhaustion of the immune system

Researchers have shown that children's T-cells capable of slowing disease progression contain the PD-1 molecule on their surface. This molecule is an immune checkpoint and its presence acts as a brake, reducing the intensity of the immune response against the virus. "The molecule is protecting children from forcing the immune system," says García-Prado. In addition, the study has identified that the T cells of these participants have characteristics similar to stem cells, known for their great potential to multiply, and that they lack signs of exhaustion. Together, these characteristics have been linked to a stronger and longer-lasting HIV-specific response.

"Normally, if you don't take HIV treatment, your immune system has to fight the virus continuously, and, in most cases, this leads to immune system exhaustion. This study has allowed us to show that this does not happen in this profile of paediatric patients. In children, the immune responses are more measured than in adults, which allows more children to better control the virus," explains Marín-López.

Therapeutic strategies that activate cellular immunity against HIV

Identifying which mechanisms promote potent and sustained antiviral responses allows new anti-HIV strategies to be designed to help control HIV without treatment in people living with HIV. In the case of paediatric patients, the study suggests that the presence of PD-1 is associated with a good cellular response against HIV. "The data suggest that these cells could be targets for new immunotherapies, activating the cellular immune response against the virus and its elimination. We have seen that their immune system has great potential as it is highly preserved and effective. This encourages us to explore new cure strategies specifically for children," concludes García-Prado.