Copy Number Variation of KIR Genes Influences HIV-1 Control
| العنوان: | Copy Number Variation of KIR Genes Influences HIV-1 Control |
|---|---|
| المؤلفون: | Barton F. Haynes, Kevin V. Shianna, Galit Alter, Jeremy J. Martinson, Andrew J. McMichael, David Goldstein, Persephone Borrow, Steven M. Wolinsky, Anna C. Need, Aids Vaccine Immunology, Norman L. Letvin, Kimberly Pelak, Jay H. Bream, Dongliang Ge, Andrea De Luca, Maureen P. Martin, Javier Martinez-Picado, Thomas J. Urban, Jacques Fellay, Sheng Feng, Amalio Telenti, Beth D. Jamieson, Mary Carrington |
| المساهمون: | NIAID Center for HIV/AIDS Vaccine Immunology, Haynes, B., Goldstein, D., Telenti, A., Ledergerber, B., Francioli, P., d'Arminio Monforte, A., De Luca, A., Castagna, A., Mallal, S., Martinez-Picado, J., Dalmau, J., Easterbrook, P., Obel, N., Cossarizza, A., Gatell, JM., Margolick, J., Phair, J., Detels, R., Rinaldo, C., Jacobson, L., Pelak, Kimberly, Need, Anna C., Fellay, Jacque, Shianna, Kevin V., Feng, Sheng, Urban, Thomas J., Ge, Dongliang, De Luca, Andrea, Martinez picado, Javier, Wolinsky, Steven M., Martinson, Jeremy J., Jamieson, Beth D., Bream, Jay H., Martin, Maureen P., Borrow, Persephone, Letvin, Norman L., Mcmichael, Andrew J., Haynes, Barton F., Telenti, Amalio, Carrington, Mary, Goldstein, David B., Alter, Galit, Castagna, Antonella |
| المصدر: | Plos Biology, vol. 9, no. 11, pp. e1001208 PLoS Biology e1001208 PLoS biology PLoS Biology, Vol 9, Iss 11, p e1001208 (2011) |
| مصطلحات موضوعية: | Immunology and Microbiology (all), Cell, Ly49 Receptor Repertoire, Kir3Ds1, Lymphocyte Activation, Virus Replication, Virus Type-1 Infection, Cohort Studies, 0302 clinical medicine, Receptors, KIR, Models, Gene Duplication, Receptors, Genetics of the Immune System, Killer Cells, Copy-number variation, Biology (General), Receptor, DNA Copy Number Variation, Genetics, 0303 health sciences, General Neuroscience, Viral Load, 3. Good health, KIR, Killer Cells, Natural, medicine.anatomical_structure, Immunological, Nk Cells, Natural, Disease Progression, DNA Copy Number Variations, HIV-1/immunology, HIV-1/physiology, Humans, Killer Cells, Natural/metabolism, Killer Cells, Natural/physiology, Models, Immunological, Receptors, KIR/genetics, Receptors, KIR/metabolism, Inhibitory Receptors, General Agricultural and Biological Sciences, KIR3DL1, Viral load, Natural-Killer-Cells, Research Article, Human, HIV-1, QH301-705.5, Immunology, chemical and pharmacologic phenomena, Biology, Settore MED/17 - MALATTIE INFETTIVE, General Biochemistry, Genetics and Molecular Biology, Molecular Genetics, 03 medical and health sciences, MHC class I, medicine, otorhinolaryngologic diseases, Genome-Wide Association Studies, Gene, 030304 developmental biology, Mhc Class-I, Neuroscience (all), Biochemistry, Genetics and Molecular Biology (all), General Immunology and Microbiology, Human Genetics, Molecular biology, Viral replication, Agricultural and Biological Sciences (all), biology.protein, Hla Class-I, Cutting Edge, Cohort Studie, 030215 immunology |
| الوصف: | The authors that the number of activating and inhibitory KIR genes varies between individuals and plays a role in the regulation of immune mechanisms that determine HIV-1 control. A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection. Author Summary There is marked intrinsic variation in the extent to which individuals are able to control HIV-1. We have identified a genetic copy number variable region (CNV) in humans that plays a significant role in the control of HIV-1. This CNV is located in the genomic region that encodes the killer cell immunoglobulin-like receptors (KIRs) and specifically affects the KIR3DS1 and KIR3DL1 genes, encoding two KIRs that interact with human leukocyte antigen B (HLA-B) ligands. KIRs are expressed on the surface of natural killer (NK) cells, which serve as important players in the innate immune response, and are involved in the recognition of infected and malignant cells through a loss or alteration in “self” ligands. We use both genetic association and functional evidence to show a strong interaction between KIR3DL1 and KIR3DS1, indicating that increasing gene counts for KIR3DL1 confer increasing levels of protection against HIV-1, but only in the presence of at least one copy of KIR3DS1. This effect was associated with a dramatic increase in the abundance of KIR3DS1+ NK cells in the peripheral blood, and strongly associated with a more robust capacity of peripheral NK cells to suppress HIV-1 replication in vitro. This work provides one of the few examples of an association between a relatively common CNV and a human complex trait. |
| وصف الملف: | application/pdf |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b53b180f2c940f7720d79379b50f783bTest https://infoscience.epfl.ch/record/178605Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b53b180f2c940f7720d79379b50f783b |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |