ccr5 mRNA 3'-UTR binds multiple protein factors, causing down-regulation of CCR5 gene expression

CCR5 acts as a co-receptor for R5-tropic human immunodeficiency virus or HIV type 1 infection. Decreasing CCR5 surface expression correlates with reduction in HIV infectivity of susceptible cells. The fundamental role of CCR5 in R5-tropic HIV infection and the few case reports of HIV cure following CCR5delta32 donor cell transplantation buttresses the continued need to investigate the regulation of CCR5 gene expression. Individuals who are homozygous for CCR5delta32 are quite resistant to HIV infection. We report here that the CCR5 3’-untranslated region or UTR region of its mRNA, which is >twice the length of the average 3’-UTR, plays a critical role in post-transcriptional gene regulation of the human CCR5 gene. Post-transcriptional mRNA regulation impacts gene function by affecting mRNA maturation, transport, and stability. Here, we demonstrate that the CCR5 3’-UTR reduced protein expression >25-fold when inserted downstream of a CMV-driven reporter and transfected into activated primary human CD4+ T cells. We also show that hnRNPA0 and hnRNPDL proteins bind to the CCR5 3’-UTR and that genomic knockout of the CCR5 3’-UTR and heteroribonucleoproteins or hnRNPs hnRNPA0, hnRNPDL, and RALY upregulated CCR5 gene expression. KO of the 3'-UTR of CCR5 increased its RNA levels in both the nucleus and cytosol. If CCR5 could somehow be down-regulated post-transcriptionally, this could have a profound impact on HIV cure efforts.