Abstract
The Duffy Antigen Receptor for Chemokines (DARC)-null trait, common among persons of African descent and associated with lower absolute neutrophil counts (ANCs), may be linked to increased risk to certain infections including HIV-1 but the underlying causes are poorly understood. We hypothesized that DARC-null-linked neutropenia may negatively impact neutrophil immunoregulatory modulation of other immune cells such as natural killer (NK) and CD8+ T cells leading to altered phenotype, functionality and homeostatic activity of these immune cells. HIV-1 uninfected (n = 20) and HIV-1 chronically infected (n = 19) participants were assessed using multi-parametric flow cytometry to determine NK and CD8+ T cell counts, phenotypic profiles, and cytokine production and degranulation. Annexin V and carboxyfluorescein succinimidyl ester (CFSE) staining were used to examine NK cell survival and NK cell and CD8+ T cell proliferation respectively. Participants were genotyped for the DARC-null polymorphism using allelic discrimination assays and ANCs were measured by full blood count. In HIV uninfected individuals, a reduction of total NK cell counts was noted in the absence of DARC and this correlated with lower ANCs. HIV uninfected DARC-null subjects displayed a less mature NK cell phenotype. However, this did not translate to differences in NK cell activation or effector functionality by DARC state. Whilst HIV-1 infected subjects displayed NK cell profiling that is typical of HIV infection, no differences were noted upon DARC stratification. Similarly, CD8+ T cells from HIV infected individuals displayed phenotypic and functional modulation that is characteristic of HIV infection, but profiling was unaffected by the DARC-null variant irrespective of HIV status. Overall, the data suggests that the DARC-null polymorphism and lower ANCs does not impede downstream cytolytic cell priming and functionality.
Highlights
The Duffy antigen receptor for chemokines (DARC), encoded by the DARC gene located on chromosome 1 (q21-q25), is a glycosylated membrane receptor expressed primarily on erythrocytes, and to some extent on vascular endothelial and neuronal cells
DARC-null linked neutropenia is associated with increased HIV-1 infection risk, its impact on HIV pathogenesis is contested
We assessed the impact of the DARC-null trait and lower absolute neutrophil counts (ANCs) on peripheral natural killer (NK) and CD8+ T cell profiles in black individuals from the HIV prevalent KwaZulu-Natal region in South Africa
Summary
The Duffy antigen receptor for chemokines (DARC), encoded by the DARC gene located on chromosome 1 (q21-q25), is a glycosylated membrane receptor expressed primarily on erythrocytes, and to some extent on vascular endothelial and neuronal cells. Expression of DARC on erythrocytes has been implicated due to the dependency of Plasmodium vivax to enter erythrocytes via DARC and establish malarial infection. A single nucleotide substitution (-46T>C) within the DARC promoter region results in selective loss of DARC expression on erythrocytes only; and confers relative resistance to certain malarial parasites. The DARC-null phenotype is common amongst African ancestry populations and a plausible consequence of positive selection pressure in regions where P. vivax has historically been endemic [1,2,3]. The molecular mechanisms for this association remain poorly understood it is postulated that DARC expression is involved in the regulation of peripheral chemokine levels that affect neutrophil chemotaxis, migration and localization [7]. The effect of the DARC-null state on disease progression is less certain, with studies on the impact of the DARC-null trait on HIV disease progression and survival advantage yielding contrasting results [12,13,14,15]
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