KIR3DS1 Conferral of Enhanced Natural Killer Cell Function in Early HIV-1 Infection

Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco; Department of Neurology, University of California, San Francisco; Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco; HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco; San Francisco, California

^* To whom correspondence should be addressed. Email: jbarbour{at}php.ucsf.edu.

	Abstract

Introduction: A flurry of recent reports on the role of activating and inhibitory forms of the Killer cell Immunoglobulin-like Receptors (KIR) in Natural Killer (NK) cell activity against HIV-1 have yielded widely divergent results. The role of the activating NK receptor encoded by the KIR3DS1 allele and its putative ligands, members of the HLA class I Bw4Ile80 cluster, in early HIV-1 disease are controversial.

Methods: We selected 60 treatment-naïve adults for study from the OPTIONS cohort of individuals with early HIV-1 infection in San Francisco. We performed NK cell functional assays measuring IFN- and CD107a expression by NK cells in the unstimulated state, and after stimulation by the MHC class I-deficient 721.221 B lymphoblastoid cell line. In addition, we measured CD38 expression (a T cell activation marker) on T and NK cells.

Results: Persons who have at least one copy of the KIR3DS1 gene had higher IFN- and CD107a expression in the unstimulated state compared to those who do not possess this gene. After stimulation, both groups experienced a large induction of IFN- and CD107a, with KIR3DS1 carriers achieving a higher amount of IFN- expression. Differences in effector activity correlating with KIR3DS1 were not attributable to joint carriage of HLA-Bw4Ile80 and KIR3DS1. We detected a partial but not complete dependence of KIR3DS1 on members of the B*58 supertype (B*57 and B*58) leading to higher NK cell function. Possessing KIR3DS1 was associated with lower expression of CD38 on both CD8⁺ T and NK cells, and with a loss or weakening of the known strong associations between CD8⁺ T cell expression of CD38 mean fluorescence intensity (MFI) and HIV-1 viral load.

Discussion: We observed that possessing KIR3DS1 was associated with higher NK cell effector functions in early HIV-1 disease, despite the absence of HLA -Bw4Ile80, a putative ligand of KIR3DS1. Carriage of KIR3DS1 was associated with diminished CD8⁺ T cell activation, as determined by expression of CD38, and a disruption of the traditional relationship between viral load and activation in HIV-1 disease, which may lead to better clinical outcomes for these individuals.