Elite HIV controllers are people who are able to control HIV replication without the need for antiretroviral treatment. They represent less than 1% of people living with HIV, but are a very interesting group to study. Recent work led by the Infectious Diseases group at Vall d'Hebron Institute of Research (VHIR) has discovered a subtype of immune cells that is characteristic of elite controllers. The results, published in the JCI Insight journal, help to understand the immunological mechanisms that favour control in these people and set the basis for developing new therapies for this infection, which currently has no definitive cure.

In recent years, numerous studies have been conducted to understand why a person with HIV is an elite controller. It is known that these patients have a very strong immune system response and, although they do not achieve complete viral clearance, they do not need antiretroviral treatment to keep the virus under control. This response is influenced by different factors in the immune system, but there are still many questions to be answered.

The Vall d'Hebron study has analysed a specific type of immune system cell: natural killer (NK) cells. "We know that NK cells are able to detect and kill HIV-infected cells quickly as a first line of defense, and we think that the response from the beginning of the infection is essential to control it", says Dr. María José Buzón, co-head of the Infectious Diseases group at VHIR. Until now, there have been few studies to analyse the NK response in elite controllers in depth.

The team compared NK cells from control people, people living with HIV with and without antiretroviral treatment, and elite controllers. NK cells from elite control people showed a more specific, precise and regulated response to the virus.

They are also better able to migrate to infected tissues and have memory cell markers. These markers allow the cells to remember previous infections and react more quickly and effectively.

A more specific and targeted response

Les células NK eliminan células infectadas por virus. Normalmente, estas células actúan de forma inespecífica, ya que pueden matar cualquier célula que detectan como anormal. Sin embargo, este trabajo ha observado que, en las personas controladoras de élite, las NK tienen una respuesta más específica. En vez de actuar NK cells kill virus-infected cells. Normally, these cells act non-specifically, as they can kill any cell they detect as abnormal. However, this work has found that, in elite controllers, NK cells have a more specific response. Instead of acting indiscriminately, they can recognise and kill cells that have been tagged with antibodies in a more targeted way.

On the other hand, the team has identified that elite driver NK cells have two markers on their surface, called NKG2C and NKG2A, which have opposite functions. While NKG2A decreases immune system activity, NKG2C acts as an activator. "We think that the fact that the cells express both receptors at the same time makes the response more balanced and targeted to eliminate HIV-infected cells, and therefore the response to the virus is more potent", explains Dr. Buzón.

Understanding the NK response will help in finding new therapies

Insights into why elite controllers have a better response to the HIV virus may help develop new therapies. "Understanding the role of NKs will help us create immunotherapy tools that target beneficial responses to control viral replication. Our goal is better therapies for people living with HIV and, in the future, a complete cure", highlights Dr. Buzón.

So far, immunotherapy and cell therapy are being investigated in the HIV field, but there are few studies with NKs. Currently, the Infectious Diseases group is working to generate more activated NK cells in animal models*, either by offering drugs that can directly modify the response of these cells, or by modifying the cells outside the body.

The work now published has been carried out in collaboration with the Instituto de Investigación Sanitaria - Fundación Jiménez Díaz and the Hospital Universitario Rey Juan Carlos in Madrid, and the Instituto de Biomedicina de Sevilla (IBiS) and has been made possible thanks to funding from the Ministry of Science, Innovation and Universities (PID2021-123321OB-100, PDC2022-133836-100).

*Institutional Declaration on the Use of Animals in Research