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5th International AIDS Society Conference on HIV Pathogenesis and TreatmentCape Town - July 19 - 22, 2009 |
THE HLA-C (GROUP 2) RESTRICTED NATURAL KILLER CELL STIMULATORY RECEPTOR, KIR2DS1, PREFERENTIALLY RECOGNIZES HIV-1 INFECTED CELLS
IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOAA101
W. Carr1,2
, V. Naranbhai2, H. Arase3, M. Carrington4, T. Ndung'u2, L. Lanier5, M. Altfeld1
1Massachusetts General Hospital / Harvard Medical School, Ragon Institute, Charlestown, United States, 2University of KwaZulu Natal- Medical School, HIV Pathogenesis Program, DDMRI, Durban, South Africa, 3Osaka University, Institute for Microbial Diseases, Suita, Japan, 4National Institutes of Health, National Cancer Institute, Frederick, United States, 5University of California at San Francisco, Microbiology and Immunology, San Francisco, United States
BACKGROUND: The mechanisms underlying innate immune protection from HIV-1 disease progression remain elusive; however, recent studies have revealed a role for Natural Killer (NK) cells, key effectors of innate immunity. In the first human whole-genome association study in HIV-1-infected individuals, Fellay and colleagues discovered a strong correlation between a single-nucleotide polymorphism (SNP) associated with elevated expression of HLA-C (rs9264942) and slower HIV-1 disease progression (Fellay et al, Science. 2007 Aug 17;317(5840):944-7). NK cells are regulated by their cell-surface expression of Killer-cell Immunoglobulin-like Receptors (KIR), some of which recognize HLA-C molecules on potential target cells. We tested the hypothesis that an HLA-C (Group 2)-specific KIR receptor (KIR2DS1) that triggers NK cell activation, selectively and preferentially recognizes HIV-1-infected cells.
METHODS: Using multicolor flow cytometry, we quantified in vitro recognition of HIV-1 VSV-g pseudotyped virally infected HLA-transfected cells by soluble recombinant KIR2DS1-Ig and KIR2DL1-Ig protein chimeras.
RESULTS: We found that KIR2DS1 bound HIV-infected (p24pos) cells significantly greater (p<0.01, T-test) than uninfected cells in an HLA-C-restricted manner. We also discovered that HIV-infection modulated HLA-C expression with infected cells expressing significantly higher levels of HLA-C (p<0.01). Relative to KIR2DL1, its inhibitory counterpart, KIR2DS1 had a higher affinity for HIV-1-infected cells than uninfected cells; however, KIR2DL1 showed greater affinity for HLA-C on primary T-cells from healthy, uninfected individuals with high and low levels of HLA-C expression.
CONCLUSIONS: This finding provides the first evidence that HIV-1 infection can modulate innate immune responses in an HLA-restricted manner. Taking into consideration the recent evidence that NK cells may have immunological memory (Sun et al, Nature. 2009 Jan 29;457(7229):557-61) we offer a new paradigm for understanding innate immune protection from HIV-1 disease. We introduce a model that blurs the line between innate and adaptive immunity; and reflects the inherent advantages of NK cell diversity, which has important implications for vaccine design.
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2009-07-22
MOAA101
Oral Abstract Session: MOAA1 - Control of HIV by Cellular Immunity
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