Impairment of CD1d-Restricted Natural Killer T Cells in Chronic HIV Type 1 Clade C Infection

Abstract

Recent studies suggest that natural killer T (NKT) cells play a role in early antiviral pathogenesis and are rapidly depleted in chronic human immunodeficiency virus type 1 (HIV-1) clade B infection. We aimed to characterize the phenotypic and functional characteristics of NKT cells in HIV-1 clade C-infected Africans at different stages of HIV-1 disease. NKT cell frequencies, subsets, and ex vivo effector functions were assessed using multiparametric flow cytometry in a cross-sectional analysis of cryopreserved peripheral blood mononuclear cells from a cohort of 53 HIV-1 clade C chronically infected South African adults with CD4 T cell counts ranging from 94 to 839 cells/ml. We observed a significant decline of NKT cell numbers in advanced HIV-1 disease as well as activation and functional impairment of NKT cells in individuals with low CD4 T cell counts. The loss of NKT cells was largely driven by a reduction in the CD4 þ and CD4 -CD8 -NKT cell subsets in advanced disease. These findings demonstrate significant impairment of the NKT cell compartment in progressive HIV-1 clade C disease that might play an important role in the modulation of immune function in HIV-1 infection.

Lessons learned from HIV-1 vaccine trials: new priorities and directions

“…However, much more must be known about the specificity of the natural killer cell receptors, particularly those used by the activating killer immunoglobulin-like receptors, before such vaccines can be designed. Also the possibility of modulating natural killer T cells 62 and regulatory T cells 63,64 , diminishing loss of the T H 17 subset of helper T cells in the gut 65 and decreasing T cell activation 66 during acute infection with HIV-1 could be worth exploring further.…”

Elevated expression of LAG-3, but not PD-1, is associated with impaired iNKT cytokine production during chronic HIV-1 infection and treatment

“…To determine the impact of iNKT LAG-3 expression, we assessed functional iNKT cytokine production capacity in the Majengo cohort. Studies of iNKT function during HIV infection and treatment in the literature suffer from lack of replication in multiple cohorts, and the only functional study performed in an African cohort reported only PMA/Io-stimulated cytokine production from ART-naïve subjects [ 33 ]. The decrease in αGalCer-induced IFNγ expression is similar to other cohorts, but the lack of functional reconstitution among ART experienced participants in this cohort is concerning [ 30 , 34 ].…”

Technical Advance: Measurement of iNKT cell responses at the single-cell level against rare HIV-1-infected dendritic cells in a mixed culture

“…These strategies comprise depletion and functional impairment of iNKT cells and interference with CD1d expression in APCs. In HIV-1-infected individuals, the iNKT cell compartment in peripheral blood is severely depleted [14–16], and even if some patients suffer from only a minimal depletion, their iNKT cells display an exhausted phenotype characterized by elevated programmed cell death protein 1 expression and reduced responsiveness to α-GalCer stimulation [17–19]. Interestingly, similar observations have been made in macaques infected with simian immunodeficiency virus, the precursor of HIV-1 [20].…”