The reasons why some patients infected with HIV-1 are capable of controlling their infection after stopping their antiretroviral therapy remain largely an enigma. In a new publication published in the journal Withresearchers from the Institut Pasteur, Inserm and AP-HP, with the funding of the Anrs-IMI, have managed to identify immune genetic characteristics specific to this category of patients.
This study, coordinated by Asier Sáez-Cirión, head of the viral reservoir unit and immune control at the Pasteur Institute, has identified that certain genetic characteristics associated with innate immunity cells (Natural Killer or NK cells) are very frequently found in post-treatment controllers. Scientists show that the presence of these genetic markers is accompanied by the existence of particular populations of NK cells which have an increased capacity to control infection. In more detail, this is the combination of a HLA-B35 with the BW4TTC2 genotype, this genetic context promoting the education of NK cells to kill HIV.
“These results support the role of NK cells in prolonged remission of HIV and could guide the development of new immunotherapy”, as Asier Saez-Cyrión, coordinator of the Visconti cohort, in a statement from the Pasteur Institute.
The “post-processing controllers” constitute a small group of patients capable of maintaining their infection by HIV-1 undetectable after stopping their treatments. Some of them have not been treated for twenty-five years, without a viral rebound. All post-treatment controllers, such as those followed in French cohorts Visconti and Primo, were discovered more or less by chance, when they were forced to interrupt their treatment for various reasons.
The question is to identify patients who could be controllers and interrupt their treatment. The initiation of early treatment, within the first days of infection, seems to promote post-treatment control of HIV-1, but the immune mechanisms are still poorly understood.
In order to identify the genetic characteristics, scientists used the data of 27 controllers of the Visconti study and those of the Primo cohort, totaling more than 1,600 HIV patients followed since the start of their infection.
A particular genotype in association with HLA-B35 antigens
HLA-B35 antigens are associated with rapid progression of HIV-1 infection. Paradoxically, researchers have found that there is a high frequency of the coding allele for HLA -B35 in controllers. But, important precision, protection is conditioned by the presence of other markers on other class 1 HLA alleles: Kir ligands (for killer immunoglobulin-like receptors) BW4 and C2. The BW4TTC2 genotype promotes the education of NK cells, which have an increased capacity to control the infection.
This work offers unpublished information on the immune mechanisms associated with HIV control without antiretroviral treatment and opens up new perspectives for the development of immunotherapy aimed at remission or healing of HIV infection.
A clinical trial, entitled Anrs 175 Rhiviera 01, has been underway since March 2023 to study the association between genetic markers of NK cells and post-interruption control of treatment. In this context, an interruption of closely monitored treatment was offered to 16 people with these genetic characteristics and which have been treated since their first infection.
In parallel, scientists are characterizing the precise influence of these genetic specificities associated with remission on the program and the function of NK cells. This approach would make it possible to develop immunotherapy to mobilize these particular cells in other people living with HIV.
For Asier Sáez-Cirión, these works “Represent a crucial step in pursuing the lasting remission of HIV infection. In a context where antiretroviral access programs are strongly threatened, new therapies that will allow people living with HIV to lead a normal life without having to take treatment even more necessary and urgent. he concludes.
