In the fight against HIV infection, natural killer (NK) cells of the immune system play a major role in eliminating the virus. Over time, however, these cells stop responding and their activity decreases significantly. A study led by the Infectious Diseases group at Vall d'Hebron Institute of Research (VHIR) has shown that the expression of the KLRG1 receptor in NK cells is related to the malfunction of these cells. The study, published in Cell Reports Medicine, shows that targeted therapies against this receptor could help eliminate the HIV virus from the body. The results were obtained in collaboration with the Infectious Diseases and Pathology Departments of the Vall d'Hebron University Hospital and La Princesa University Hospital (Madrid).

Although antiretroviral therapies help control HIV, total elimination is still a challenge for medicine, as the virus persists in an inactive form in cells in the blood or lymphoid tissues that are not accessible to the immune system: they are the cellular reservoirs. NK cells have a high capacity to kill virus-infected cells, but HIV infection alters them and reduces their cytotoxic activity, i.e. their ability to kill infected cells. "Understanding the role of NK cells in HIV elimination may help to develop new therapies aimed at boosting the immune system and helping to eliminate the virus reservoir," explains Dr. María José Buzón, co-head of the Infectious Diseases group at VHIR and leader of the study.

The study shows that chronic HIV infection increases the number of NK cells expressing the KLRG1 receptor, which inhibits the cytotoxic activity and proliferation of NK cells: "The expression of KLRG1 prevents a correct response against the virus because, in this situation, the immune system, especially NK cells, does not function properly," explain Dr. Antonio Astorga and David Perea, first authors of the study from the Infectious Diseases group. In addition, the study also shows that KLRG1 is also expressed by CD4+ T cells that are infected by the virus.

Once KLRG1 was identified, the researchers tested the use of antibodies to block it in cell culture. In this way, NK cells were shown to re-establish their ability to kill HIV-infected cells. In addition, inhibition of this receptor was shown to reactivate dormant HIV reservoir cells so that they can again be recognised and killed by NK cells and attacked by antiretroviral therapy. "Our results therefore lay the bases for a new therapeutic strategy against HIV infection through immunotherapy," concludes Dr. María José Buzón.

The study has been made possible thanks to the support of “la Caixa” Foundation, FEDER funds, the Instituto de Salud Carlos III, the Gilead grants and La Marató de TV3.