CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

Multiple genome-wide studies have identified associations between outcome of HIV infection and polymorphisms in/around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164 A/G, is unknown. We found that rs1015164, located 34KB downstream of CCR5, marks variation in an ATF1 binding site that controls expression of the antisense long non-coding RNA CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4(+) T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3’ untranslated region, protecting CCR5 mRNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4(+) T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a long non-coding RNA affects level of HIV infection and disease progression.