Interindividual differences in CCR5 expression levels are a critical determinant of HIV-1 susceptibility and progression rate to AIDS. There is strong evidence indicating that these differences could be ascribed to genetic variation in the CCR5 locus. Genetic variability in CCR5 also has been implicated in susceptibility to other infectious and systemic diseases that are relevant to the veteran population. Delineating the mechanisms that modulate intersubject differences in CCR5 expression levels is thus of indisputable importance and significance for understanding pathogenesis of HIV-1 infection and other diseases such as diabetes. There is strong in vitro and in vivo evidence that the polymorphic residues at positions -2135 and -2459 in the CCR5 cis-regulatory region have a dominant effect on its expression. Our studies in this proposal are designed to elucidate the mechanisms by which differential binding of transcription factors to these polymorphisms leads to allele-specific modulation of gene expression resulting in variable CCR5 levels.
Specific Aim 1 will test the hypothesis that disease-modifying CCR5 alleles exhibit variable transcription factor binding repertoire.
Specific Aim 2 will determine whether the TFs that bind differentially to CCR5 SNPs also influence variable CCR5 expression. We will employ state-of-the art and innovative proteomic and molecular techniques to dissect the complex interactions between the TF binding to CCR5 polymorphisms which lead to variability in CCR5 expression levels. These studies have translational (benchAEbedside) utility as they will identify mechanisms of variable CCR5 expression that may impact on susceptibility to HIV-1/AIDS and other diseases. These molecular studies will capitalize on the vast experience of the PI in transcriptional gene regulation and collaborative efforts with Dr. Jarrett, a leading authority in transcriptional proteomics. There are several down-stream, value-added features of this application: (a) although the studies outlined in this grant will focus on the transcriptional proteomics of CCR5, they are widely applicable to a broad array of genes for which regulatory variation has been implicated in human disease;(b) the results may identify new pathways to target CCR5 expression, thus resulting in development of new therapies;(c) identification of additional genetic determinants that influence CCR5 expression levels. The outlined studies might lead to development of effective treatment strategies and improved vaccination trials and are in line with the goals of VA's Genomic Medicine Initiative.

Public Health Relevance

The studies proposed will provide novel insights into the mechanisms that are responsible for interindividual differences in CCR5 expression and HIV-1 susceptibility. This information could help in developing novel anti-HIV therapies as well as in evaluation of vaccine efficacy.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Infectious Diseases A (INFA)
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South Texas Veterans Health Care System
San Antonio
United States
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Gornalusse, German G; Mummidi, Srinivas; Gaitan, Alvaro A et al. (2015) Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor. Proc Natl Acad Sci U S A 112:E4762-71
Somanna, Naveen K; Yariswamy, Manjunath; Garagliano, Joseph M et al. (2015) Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cell Signal 27:1928-38
Narasimhan, Madhusudhanan; Rathinam, Marylatha; Riar, Amanjot et al. (2013) Programmed cell death 4 (PDCD4): a novel player in ethanol-mediated suppression of protein translation in primary cortical neurons and developing cerebral cortex. Alcohol Clin Exp Res 37:96-109
Murray, David R; Mummidi, Srinivas; Valente, Anthony J et al. (2012) ?2 adrenergic activation induces the expression of IL-18 binding protein, a potent inhibitor of isoproterenol induced cardiomyocyte hypertrophy in vitro and myocardial hypertrophy in vivo. J Mol Cell Cardiol 52:206-18
Pham, Minh-Hieu T; Bonello, Gregory B; Castiblanco, John et al. (2012) The rs1024611 regulatory region polymorphism is associated with CCL2 allelic expression imbalance. PLoS One 7:e49498
Bonello, Grégory B; Pham, Minh-Hieu; Begum, Kazi et al. (2011) An evolutionarily conserved TNF-alpha-responsive enhancer in the far upstream region of human CCL2 locus influences its gene expression. J Immunol 186:7025-38
Jiang, Daifeng; Mummidi, Srinivas; Ahuja, Sunil K et al. (2011) CCR5 promoter haplotype transcription complex characterization. J Health Care Poor Underserved 22:73-90
Mamtani, Manju; Mummidi, Srinivas; Ramsuran, Veron et al. (2011) Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population. J Infect Dis 203:1590-4