Differential microRNA regulation of HLA-C expression and its association with HIV control : Nature : Nature Publishing Group

Differential microRNA regulation of HLA-C expression and its association with HIV control
Smita Kulkarni,1, 2, 8 Ram Savan,3, 8 Ying Qi,1, 2 Xiaojiang Gao,1, 2 Yuko Yuki,1, 2 Sara E. Bass,1 Maureen P. Martin,1, 2 Peter Hunt,4 Steven G. Deeks,4 Amalio Telenti,5 Florencia Pereyra,2 David Goldstein,6 Steven Wolinsky,7 Bruce Walker,2 Howard A. Young3 & Mary Carrington1, 2

These authors contributed equally to this work.
Smita Kulkarni & Ram Savan

Affiliations
Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA
Smita Kulkarni,Ying Qi,Xiaojiang Gao,Yuko Yuki,Sara E. Bass,Maureen P. Martin &Mary Carrington
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts 02114, USA
Smita Kulkarni,Ying Qi,Xiaojiang Gao,Yuko Yuki,Maureen P. Martin,Florencia Pereyra,Bruce Walker &Mary Carrington
Cancer and Inflammation Program, Laboratory of Experimental Immunology, NCI-Frederick, Frederick, Maryland, 21702 USA
Ram Savan &Howard A. Young
San Francisco General Hospital AIDS division, University of California, San Francisco, California 94110, USA
Peter Hunt &Steven G. Deeks
Institute of Microbiology, University of Lausanne, Lausanne 1011, Switzerland
Amalio Telenti
Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA
David Goldstein
Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
Steven Wolinsky

Contributions
S.K. and R.S. performed and evaluated the miRNA experiments. S.K., R.S., H.A.Y. and M.C. designed the study. M.C. directed the study. S.K., R.S. and M.C. wrote the manuscript. X.G., Y.Y., S.B. and M.M. genotyped HLA. Statistical analysis was performed by Y.Q. The clinical samples and data were contributed to by P.H., S.G.D., D.D., A.T., D.G., S.W., F.P. and B.W. Intellectual input was provided by all authors.

Competing financial interests
The authors declare no competing financial interests.

Corresponding author
Correspondence to: Mary Carrington


Journal name: Nature
Year published: (2011)
DOI: doi:10.1038/nature09914
Received12 March 2010
0Accepted10 February 2011
Published online17 April 2011


The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism1, lower expression on the cell surface2, 3, and more extensive ligand–receptor interactions with killer-cell immunoglobulin-like receptors4. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed −35) associates with control of HIV5, 6, 7, and with levels of HLA-C messenger RNA transcripts8 and cell-surface expression7, but the mechanism underlying its varied expression is unknown. We proposed that the −35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C7. Here we show that variation within the 3′ untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3′ UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.


Figures at a glance

Figure 1: Variation in the HLA-C 3′ UTR differentially affects the expression of a reporter gene.
a, b, Full-length 3′ UTRs of various HLA-C alleles cloned into luciferase (LUC) reporter constructs were transfected into B721.221 cell lines and the stability of the mRNA was estimated by dual luciferase reporter assays. The normalized luciferase activity is presented as fold change of relative light units (RLU). The data represent six replicates in each experimental group, the mean ± standard error (s.e.) are depicted as horizontal and vertical bars for each group, respectively, and one of three comparable experiments performed is shown. Non-parametric Wilcoxon–Mann–Whitney tests were used for statistical comparisons and two-tailed P values are indicated. NS, not significant. a, Schematic representations of the luciferase reporter constructs used in this study. Sv40, Simian virus 40. b, Fold change in luciferase activity of 3′ UTRs of HLA-C alleles as compared to that of Cw*0602.

Figure 2: Disruption of miR-148a target site rescues suppression.
Differential microRNA regulation of HLA-C expression and its association with HIV control : Nature : Nature Publishing Group





SIDA
Identificado un mecanismo de regulación que controla el virus del sida
JANO.es y agencias · 18 Abril 2011 13:10

.Científicos norteamericanos creen que el hallazgo podría conducir a nuevos métodos de manipulación del sistema inmunitario en el tratamiento de la enfermedad humana.


La variación en la expresión de la molécula HLA-C, que se asocia al control del VIH, está regulada por un microARN, según un estudio del Instituto Nacional del Cáncer en Frederick (Estados Unidos) que se publica en la edición digital de Nature. Este descubrimiento podría conducir a nuevos métodos de manipulación del sistema inmunitario en el tratamiento de la enfermedad humana.

El HLA-C es una molécula con un importante papel en el sistema inmunitario. Una variante de HLA-C producida por un polimorfismo de nucleótido simple (SNP), conocido como -35 SNP, se ha asociado a la carga de VIH y la progresión del sida. Sin embargo, se desconoce el mecanismo que subyace a su expresión variada.

Los investigadores, dirigidos por Mary Carrington, sugieren que -35 SNP es un marcador de otro polimorfismo en la región 3' sin traducir del gen que afecta a la expresión del HLA-C.

Los autores muestran que la variación en esta región regula la unión del microARN que afecta a los niveles de varios alelos de HLA-C. Los datos por ello indican que el microARN podría tener un importante papel en el control del VIH a través de la regulación de HLA-C.

Nature 2011; doi:10.1038/nature09914
Differential microRNA regulation of HLA-C expression and its association with HIV control : Nature : Nature Publishing Group

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