Control of HIV Through a Cell Surface Protein, HLA-C, and Its Complicated Regulation
CCR researchers found evidence that the -35 SNP marks the presence of a variant in the HLA-C miR-148a binding site that directly determines whether or not there is an increase in expression of HLA-C.
Biological systems are complex. In many cases, the actions of various components are intertwined, and the effects of manipulating one component may actually be driven by that molecule’s relationship with a different component. Deciphering this kind of regulation is important for identifying the best therapeutic targets. An example of such complexity can be seen in the control of HIV/AIDS.
Progression of HIV infection to AIDS is known to be influenced by the genetic makeup of the host individual. Variation in the area of the host genome called the HLAclass I loci has a stronger influence on HIV-1 disease outcomes than any other genetic locus. One HLA locus, HLA-C, was recently shown to be associated with progression to AIDS after HIV infection and control of HIV viral load. Individuals with high-expressing HLA-C loci progress more slowly to AIDS and control levels of HIV better than individuals with low HLA-C expressing loci. A single change in the sequence of DNA 35Kb upstream of the HLA-C gene—known as the -35Kb single-nucleotide polymorphism (SNP)—has been associated with altered levels of HLA-Cbut, to date, researchers have not determined if and how the -35Kb SNP has a direct effect on the HLA-C locus.
As reported in a recent issue of Nature, a team of scientists that included postdoctoral fellows Smita Kulkarni, Ph.D., who works with Mary Carrington, Ph.D., and Ram Savan, Ph.D., who works with Howard Young, Ph.D., in CCR’s Laboratory of Experimental Immunology, set out to study the regulation of HLA-C and found that the -35 SNP does not directly affect HLA-C levels but, rather, correlates with the presence of another DNA sequence variant that affects its expression. They found this by studying how microRNAs (miRNAs) regulate HLA-C expression. MicroRNAs are a class of non-protein-coding RNAs that are estimated to regulate 30 percent of all genes in animals by binding to specific messenger RNA molecules (mRNA, the product of gene expression) and preventing translation of the mRNA into protein. By sequencing and testing many different variants of the HLA-C locus, the researchers found that a particular miRNA (miR-148a) does not bind to its target site in certain variants, resulting in high HLA-C expression. Using different naturally occurring as well as artificially constructed variants of the HLA-C mRNA at the miR-148a binding site and nearby regions, they also demonstrated that nucleotide variations in the region differentially regulate HLA-C expression.
Though the -35 SNP is associated with control of HIV, no direct causal relationship between the -35 SNP and HLA-C expression has been established. Through a study of genetic variation in 1,760 HIV-infected European-American individuals, the researchers found evidence that the -35 SNP marks the presence of a variant in the HLA-CmiR-148a binding site that directly determines expression of HLA-C.
Multiple factors, including the -35 SNP and miR-148a binding, may be involved in regulating the expression levels of HLA-C and control of HIV. An understanding of these intricate details will help in developing new strategies for targeted drug development for treating AIDS.Summary Posted: 12/2011
Differential microRNA regulation of HLA-C expression and its association with HIV control Smita Kulkarni, Ram Savan, Ying Qi, Xiaojiang Gao, Yuko Yuki, Sara E. Bass, Maureen P. Martin,Peter Hunt, Steven G. Deeks, Amalio Telenti, Florencia Pereyra, David Goldstein, Steven Wolinsky, Bruce Walker, Howard A. Young & Mary Carrington. Nature (2011) doi:10.1038/nature09914 http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature09914.html Reviewed by Donna Kerrigan