title: Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection.
abstract: 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 human immunodeficiency virus type 1 (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 is controversial. 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 gamma interferon (IFN-gamma) and CD107a expression by NK cells in the unstimulated state and after stimulation by the major histocompatibility complex 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. Persons who have at least one copy of the KIR3DS1 gene had higher IFN-gamma 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-gamma and CD107a, with KIR3DS1 carriers achieving a greater amount of IFN-gamma 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 the members of 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 and the HIV-1 viral load. 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.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Long
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D008297:Male; D054349:Receptors, KIR3DS1 / Q000235:genetics / Q000276:immunology*; D012495:San Francisco; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; D052118:Lysosomal-Associated Membrane Protein 1; D054349:Receptors, KIR3DS1; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1