Abstract
Natural killer (NK) cells are major effectors of the innate immune response. Despite an overall defect in their function associated with chronic human immunodeficiency virus (HIV) infection, their role in primary HIV infection is poorly understood. We investigated the modifications of the NK cell compartment in patients from the ANRS-147-Optiprim trial, a study designed to examine the benefits of intensive combination antiretroviral therapy (cART) in patients with acute or early primary HIV infection. Multiparametric flow cytometry combined with bioinformatics analyses identified the NK phenotypes in blood samples from 30 primary HIV-infected patients collected at inclusion and after 3 months of cART. NK phenotypes were revealed by co-expression of CD56/CD16/NKG2A/NKG2C and CD57, five markers known to delineate stages of NK maturation. Three groups of patients were formed according to their distributions of the 12 NK cell phenotypes identified. Their virological and immunological characteristics were compared along with the early outcome of cART. At inclusion, HIV-infected individuals could be grouped into those with predominantly immature/early differentiated NK cells and those with predominantly mature NK cells. Several virological and immunological markers were improved in patients with mature NK profiles, including lower HIV viral loads, lower immune activation markers on NK and dendritic cell (DC), lower levels of plasma IL-6 and IP-10, and a trend to normal DC counts. Whereas all patients showed a decrease of viremia higher than 3 log10 copies/ml after 3 months of treatment, patients with a mature NK profile at inclusion reached this threshold more rapidly than patients with an immature NK profile (70 vs. 38%). In conclusion, a better early response to cART is observed in patients whose NK profile is skewed to maturation at inclusion. Whether the mature NK cells contributed directly or indirectly to HIV control through a better immune environment under cART is unknown. The NK maturation status of primary infected patients should be considered as a relevant marker of an immune process contributing to the early outcome of cART that could help in the management of HIV-infected patients.
Highlights
Natural killer (NK) cells are one of the major innate immune components involved in the rapid response of the host to invading virus [1]
We investigated the phenotypes of differentiation of NK cells with multiparametric cytometry using CD56, CD16, NKG2A, CD57, and NKG2C, known to delineate sequential stages of NK cell maturation [2, 4]
They included several groups differentially expressing NKG2A and CD57, two markers linked to immaturity or maturity, respectively, and NKG2C, a NK cell receptor expanded during CMV infections
Summary
Natural killer (NK) cells are one of the major innate immune components involved in the rapid response of the host to invading virus [1] Their function is probably crucial at the time of infection and can impact the quality of adaptive immune responses and the overall outcome of infections. The co-expression of CD56, CD16, NKG2A, NKG2C, and CD57 delineates sequential stages of the NK cell maturation process suggesting the acquisition of typical effector functions. Because cell populations expressing unexpected combinations of markers might be expanded in pathological conditions, new bioinformatics methods were applied to analyze multiparametric cytometry data in an unsupervised approach [22] This allowed the identification of a relationship between profiles of NK cells skewed to immaturity or maturity and virological and immune parameters reached naturally a few weeks after infection and after early cART
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