Innate-like and NK Signatures in Chronic-Treated HIV Infection INSTINCT-HIV

Infection with the human immunodeficiency virus (HIV) is a chronic condition requiring lifelong antiretroviral therapy (ART). Despite prolonged virological control under suppressive ART, HIV persists in the form of a stable viral reservoir known as the 'integrated' reservoir, mainly localised in CD4+ memory T cells, which constitutes the obstacle to a functional or sterilising cure of the infection. The immunological mechanisms involved in the control, stability or gradual depletion of this reservoir are still not fully understood.

Among the cellular populations of the innate immune system, Natural Killer (NK) cells play an important role in the trajectory of the reservoir by having the ability to eliminate HIV-infected cells. However, several studies have shown that these NK cells exhibit variable capabilities in eliminating such cells, suggesting that inter-individual heterogeneity in innate immune responses may contribute to the observed differences in the size and persistence of the viral reservoir in people living with HIV (PLHIV) on long-term suppressive ART. Functionally, interactions between NK cell receptors and class I HLA molecules (HLA I) strongly modulate the education, repertoire and effector functions of NK cells, indicating that the immunogenetics of the host's HLA I alleles is therefore a major determinant of this variability. Certain receptor/HLA I combinations, notably receptors known as KIRs, have been associated with differences in the progression of HIV infection and immunovirological control. Consequently, their role in the dynamics of the viral reservoir during prolonged suppressive ART needs to be explored. Finally, biological sex significantly influences anti-HIV immune responses, with females showing a favourable response. Whilst sex differences in NK cell function and immune activation have been described, the impact of biological sex on the dynamics of the HIV reservoir under prolonged suppressive ART remains largely unknown and requires further investigation