CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Genome-wide studies link CCR5 gene polymorphisms to human immunodeficiency virus (HIV) infection outcomes.
• The functional mechanism behind the strongest association, rs1015164A/G, remains unclear.

Purpose of the Study:

• To elucidate the functional basis of the rs1015164A/G polymorphism in HIV infection.
• To investigate the role of long noncoding RNAs (lncRNAs) in regulating CCR5 expression and HIV susceptibility.

Main Methods:

• Investigated the rs1015164A/G polymorphism's effect on transcription factor binding sites.
• Assessed the impact of CCR5AS (antisense long noncoding RNA) expression on CCR5 levels in CD4+ T cells.
• Examined the interaction between CCR5AS, Raly, and CCR5 messenger RNA (mRNA) stability.
• Evaluated the effect of CCR5AS inhibition on HIV infection in vitro.

Main Results:

• rs1015164 variation affects an activating transcription factor 1 binding site controlling CCR5AS expression.
• CCR5AS expression levels directly correlated with CCR5 expression on CD4+ T cells.
• CCR5AS protects CCR5 mRNA from degradation by interfering with Raly binding.
• Inhibition of CCR5AS reduced CCR5 expression and diminished HIV infection of CD4+ T cells.

Conclusions:

• The lncRNA CCR5AS plays a critical role in regulating CCR5 expression and susceptibility to HIV infection.
• This study provides a functional explanation for a significant genome-wide association with HIV disease.
• Understanding lncRNA-mediated regulation offers new insights into HIV pathogenesis and potential therapeutic targets.