Lack of association of KIR2DL1-R245 and KIR2DL1-C245 with HIV-1 control in black South Africans with HLA-C2

Abstract

Activating/inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs) partly regulate Natural Killer (NK) cells. KIR2DL1 allotypes with cysteine at position-245 (KIR2DL1-C²⁴⁵) express at lower levels and demonstrate weaker inhibitory signaling compared to allotypes with arginine at position-245 (KIR2DL1-R²⁴⁵). The functional consequence of either allotype in infectious diseases is unknown. Since NK cells mediate antiviral immunity, we investigated KIR2DL1-R²⁴⁵ and KIR2DL1-C²⁴⁵ in association with HIV-1 virological control in untreated immunocompetent black South Africans. Allotype carriage, determined by KIR2DL1 sequencing, was similar between uninfected South Africans (n = 104) and other black African populations, but differed significantly from Europeans, while no significant differences were noted between uninfected and HIV-1-infected individuals (n = 52). KIR2DL1 expression, measured by flow cytometry, in uninfected individuals showed higher KIR2DL1-R²⁴⁵ expression compared to KIR2DL1-C²⁴⁵ in white donors (n = 27), while black donors (n = 21) generally expressed lower levels of both allotypes. KIR2DL1 expression was reduced in HLA-C2 carriers, most evident in black HLA-C2/C2 donors. KIR2DL1-R²⁴⁵ and KIR2DL1-C²⁴⁵ did not associate with viral load when HLA-C2 ligands were present, however in HLA-C1 homozygotes, individuals with only KIR2DL1-R²⁴⁵, showed lower viral loads compared to carriers of both allotypes. The lack of association of KIR2DL1-R²⁴⁵ or KIR2DL1-C²⁴⁵ with HIV-1 control in HLA-C2 carriers may relate to lower KIR2DL1 expression levels in a population with high HLA-C2 prevalence.

Keywords: Black South African population; HIV-1; HLA-C2; KIR2DL1-C(245); KIR2DL1-R(245).