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Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

2015; National Academy of Sciences; Volume: 112; Issue: 34 Linguagem: Inglês

10.1073/pnas.1423228112

1091-6490

Germán G. Gornalusse, Srinivas Mummidi, Álvaro Andrés Gaitán, Fabio Jimenez, Veron Ramsuran, Anabela C.P. Picton, Kristen C Rogers, Muthu Saravanan Manoharan, Nymisha Avadhanam, Krishna K. Murthy, Hernan Martinez, Angela Molano Murillo, Z. A. Chykarenko, Richard Hutt, Demetre C Daskalakis, Ludmila Shostakovich-Koretskaya, Salim S. Abdool Karim, Jeffrey N. Martin, Steven G. Deeks, Frederick Hecht, Elizabeth Sinclair, Robert A. Clark, Jason F. Okulicz, Fred Valentine, Neil Martinson, Caroline T. Tiemessen, Thumbi Ndung’u, Peter W. Hunt, Weijing He, Sunil K. Ahuja,

Immune Cell Function and Interaction

Significance Levels of CC chemokine receptor 5 (CCR5) on T cells are a critical factor influencing HIV/AIDS susceptibility. DNA methylation is an epigenetic feature associated with lower gene expression. Here we show that the DNA methylation status of CCR5 cis -regulatory regions ( cis -regions) correlates inversely with CCR5 levels on T cells. T-cell activation induces demethylation of CCR5 cis -regions, upregulating CCR5 expression. Higher vs. lower sensitivity of CCR5 cis -regions to undergoing T-cell activation-induced demethylation is associated with increased vs. decreased CCR5 levels. Polymorphisms in CCR5 cis -regions that are associated with increased vs. decreased HIV/AIDS susceptibility are also associated with increased vs. decreased sensitivity to activation-induced demethylation. Thus, interactions among T-cell activation, CCR5 epigenetics, and genetics influence CCR5 levels on T cells and, by extension, HIV/AIDS susceptibility.