Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) 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 messenger RNA 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 lncRNA affects HIV infection and disease progression.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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The project was supported by NIAID (grant nos AI120900 and AI140956 to S.K.), HU-CFAR (to S.K.), Cowles fellowship (to S.S.), institutional funds from the Texas Biomedical Research Institute and the Ragon Institute of MGH, MIT and Harvard. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory (contract no. HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab and Center for Cancer Research. See extended acknowledgements in Supplementary Information for full details.
The authors declare no competing interests.
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Integrated supplementary information
Supplementary Figure 1 The rs1015164 SNP marking expression of CCR5AS associates independently with HIV viral load in Japanese subjects.
a, Sanger sequencing was carried out to determine rs1015164 genotypes of 504 HIV infected Japanese subjects (GG=51%, AG=44% and AA=5%). b, Patients with AA genotype showed significantly higher HIV viral load as compared to the patients with GG or AG/GG genotypes.
Supplementary Figure 2 Gating strategy for CD4+ T cell subsets and characterization of CCR5AS transcript expression.
a, Flow cytometry gating strategy used to characterize CD4+ T cell subsets. b, rs1015164A marks high expression of CCR5AS (ENSG00000223552.1) in blood, Colon, Adipose-Visceral, Heart left ventricle, Lung, Adipose-subcutaneous, Brain (https://www.gtexportal.org/). c, Amplification of the 3’ and 5’ ends of the CCR5AS transcript uncovered the presence of two distinct isoforms: a long isoform of 699bp and a 431bp short form that is differentially spliced and lacks exon 2. d, Total RNA was extracted from the cytoplasmic and nuclear fractions of primary CD4+ T cells and Hut-78 cells. Relative expression levels of CCR5AS in the cytoplasm (black) vs. the nucleus (white) were assessed using qPCR. Unspliced β-actin mRNA and spliced GAPDH mRNA, which are enriched in the nuclear and cytoplasmic fractions, respectively, were used as controls to assess purity of the extracts.
a, Peripheral blood CD4+ T cells were transfected with 300 nm siRNA targeting CCR5AS (siLnc1) or a control siRNA (siCon1). CCR5AS mRNA was measured 24 hours post-transfection. Cells transfected with siLnc1 showed 70–80% downregulation of CCR5AS mRNA as compared to the siCon1 treated cells. b, Cells transfected with siLnc2, which targets a region of CCR5AS distinct from that of siLinc1, showed 60–70% downregulation of CCR5AS mRNA as compared to siCon2 treated cells. c, Cells transfected with siLnc2 showed lower CCR5 mRNA expression as compared to the siCon2 transfected cells. d, Cell surface expression of CCR5 was measured 24 hours after siRNA transfection. The cells transfected with siLnc2 (red curve) showed lower CCR5 cell surface expression as compared to the siCon2 (blue curve) transfected cells. The open black curve depicts isotype control. Fold change in expression levels was calculated as the ratio of mean fluorescence intensity (MFI) of CCR5 vs isotype control. A histogram of one of 6 comparable experiments performed is shown for each silencing. The mean ± SE (n = 6) are depicted as horizontal and vertical bars for each group, respectively. Paired t test was used for statistical comparisons and two tailed p value is indicated. e, CD4+ T cells were transfected with the in vitro transcribed long form of CCR5AS [CCR5AS(L)] or scrambled RNA controls (ConRNA). CCR5 mRNA expression was measured 24 hours post-transfection. Cells transfected with CCR5AS(L) showed higher CCR5 mRNA levels as compared to the scrambled control. f, The cell surface expression of CCR5 in cells transfected with CCR5AS(L) (red curve) was higher as compared to the scrambled control (blue curve) transfected cells. The grey curve depicts isotype control. Fold change in expression levels was calculated as the ratio of mean fluorescence intensity (MFI) of CCR5 vs isotype control. A histogram of one of 6 comparable experiments performed is shown. Statistics are as described in (d).
Supplementary Figure 4 CCR5AS silencing inhibits CCR5 expression in Hut-78 cells by reducing CCR5 mRNA stability.
a, Hut-78 cells were transfected with 300 nm siRNA targeting CCR5AS (siLnc1) or control siRNA (siCon1). CCR5 mRNA was measured 24 hours post-transfection. Cells transfected with siLnc1 showed lower expression as compared to the controls. b, Cell surface expression of CCR5 on Hut-78 cells was measured 48 hours post-transfection. The cells transfected with siLnc1 (red curve) showed lower cell surface expression as compared to siCon1 transfected cells (blue curve). The gray curve depicts isotype controls. Fold change in expression levels was calculated as the ratio of mean fluorescence intensity (MFI) of CCR5 vs isotype control. A histogram of one of three comparable experiments performed is shown. The mean ± SE (n = 3) are depicted as horizontal and vertical bars for each group, respectively. Paired t test was used for statistical comparisons and two tailed p value is indicated. c, CCR5 mRNA RNA decay was determined by 5-Ethylene uridine (EU) pulse-labeling of RNA using the Click-iT Nascent RNA Capture Kit. Hut-78 cells were transfected with siCon1 or siLnc1 and pulsed with EU. Eighteen hours after EU-pulsing, the cells were washed, supplemented with fresh growth medium and harvested at one hour intervals for 4 hours. Total RNA was isolated from cells and quantitated. The EU-labeled RNA was biotinylated, precipitated, and captured using streptavidin coated magnetic beads as per the manufacturer’s protocol. The RNA captured on beads was used for cDNA synthesis and qPCR analysis. Data are represented as relative expression levels of CCR5 mRNA in the siCon1 or siLnc1 transfected cells. The mRNA half-life (50% mRNA remaining, t1/2) for the CCR5 mRNA in siCon1 (3h) was higher as compared to the siLnc1 treated cells (2.2h). Data represent mean ± SEM. One of two comparable experiments performed is shown. Paired t test was used for statistical comparisons and one tailed p value is indicated.
Supplementary Figure 5 CCR5AS mediated regulation of CCR5 expression is independent of shared miRNA binding sites.
Hut-78 cells were transfected with in vitro transcribed CCR5AS or scrambled RNA controls and cell surface expression of CCR5 was measured 48h post-transfection. a, b, Cells transfected with the wild type long (L) form (a) or the short (S) form (b) of CCR5AS transcript showed higher CCR5 cell surface expression. c,d,e, Cells transfected with CCR5AS mutant transcripts with disruption in binding sites of miR-1224 (c), miR-197 (d), or both (e) showed higher CCR5 cell surface expression as compared to the respective controls. Surface expression of cells transfected with CCR5AS are shown as various colored curves whereas the scrambled RNA controls are represented by blue curves. The open black curves depict isotype control. A histogram of one of three comparable experiments performed is shown for each overexpression. f, Fold change in CCR5 expression levels was calculated as the ratio of mean fluorescence intensity (MFI) when staining with CCR5-specific antibody vs isotype control. g, Fold changes in CCR5 mRNA upon transfection with the various forms of the CCR5AS mRNA are shown. CCR5 mRNA levels were normalized to GAPDH mRNA and the mean ±SE (n=3) are depicted as horizontal and vertical bars for each group, respectively. CCR5AS RNA transfections were compared to those with Control RNA and an unpaired t test was used for statistical comparisons with two tailed p value indicated.
a, Western blot analysis was performed to confirm the presence of Raly protein in the (AS) pulldown as compared to the SC pulldown. b, In silico prediction of the interaction between the long (left) and short (right) forms of the CCR5AS transcript and Raly protein was done using a freely available algorithm (http://service.tartaglialab.com/newsubmission/globalscore), which integrates properties of protein and RNA structures into overall binding propensity. Global score predicts global and local interactions between RBP and lncRNA. A high interaction score (≈1) predicts a strong interaction between Raly protein and CCR5AS transcript. c, A Myc-tagged Raly protein sequence was transfected in Hut-78 cells. The c-Myc tagged protein was immunoprecipitated using anti-Myc antibody coated magnetic beads, but not with nonspecific IgG, as confirmed by Western blot. d, The Hut-78 cell line was transfected with either control siRNA (siCon) or Raly siRNA (siRaly). Cells were harvested at 48h and 72h post-transfection. Western blot analysis showed downregulation of Raly after 72h. Alpha tubulin was used as the housekeeping control. e CCR5 3’UTR was cloned downstream of Renilla luciferase into a dual luciferase reporter psicheck2 vector. The Raly binding site in the CCR5 3’UTR sequence is indicated by a red bar. f, Hut-78 cells were transfected with a vector encoding Myc-tagged Raly protein (Raly-Myc) along with either Control siRNA (siCon1) or CCR5AS siRNA (siLnc1). Cells were lysed and RNA immunoprecipitation was carried out using anti-Myc antibody (Raly-IP) or control IgG (IgG-IP). Precipitation of Raly protein by anti-Myc antibody, but not control IgG, was confirmed by Western blot. Input represents straight lysate (that is no immunoprecipitation). g, Fold enrichment of CCR5AS in the pulldown was determined using qPCR. CCR5AS was enriched in the Raly pulldown (Raly-IP) as compared to IgG in the siCon1 treated cells. No enrichment of CCR5AS was observed in the Raly pulldown of cells transfected with siLnc1. h, CCR5 mRNA decay was determined by 5-Ethylene uridine (EU) pulse-labeling of RNA using the Click-iT Nascent RNA Capture Kit. Hut-78 cells were transfected with siRaly or siCon and pulsed with EU after 60 hours. Eighteen hours after EU-pulsing, the cells were washed, supplemented with fresh growth medium and harvested at one hour intervals for 4 hours. Total RNA was isolated from cells and quantitated. The EU-labeled RNA was biotinylated, precipitated, and captured using streptavidin coated magnetic beads as per the manufacturer’s protocol. The RNA captured on beads was used for cDNA synthesis and qPCR analysis. Data are represented as relative expression levels of CCR5 mRNA in the siCon or siRaly transfected cells. The mRNA half-life (50% mRNA remaining, t1/2) for the CCR5 mRNA in siRaly (4h) was higher as compared to the siCon treated cells (2.9h).
a, Schematic presentation of experimental design. Peripheral blood CD4+ T cells were transfected with siRNA. Twenty-four hours post transfection, the cells were infected with VSV-G pseudotyped HIV virus encoding GFP or CCR5-tropic HIV virus encoding GFP. The proportions of VSV-G/GFP+ or CCR5-tropic/GFP+ cells were determined by flow cytometry. b, c, d Flow cytometry gating strategy is represented here uninfected (b), and VSV-G/GFP (c) or CCR5-tropic/GFP (d) virus infected cells of a single experiment. Debris was excluded based on light scattering characteristics. Proportions of VSV-G/GFP+ or CCR5-tropic/GFP+ cells were analyzed for the cells in P1 gate. The uninfected cells did not show GFP+(R1 gate). e, f Peripheral blood CD4+ T cells from 8 unrelated donors were transfected with control siRNA (siCon1) or CCR5AS siRNA (siLnc1). Twenty-four hours post transfection, the cells were infected with VSV-G/GFP (e) or CCR5-tropic/GFP virus (f). The proportions of VSV-G/GFP+ cells in the siLnc1 treated cells were comparable to that of the siCon1 treated cells, but silencing of CCR5AS diminished infection of CD4+ T cells with the CCR5-tropic/GFP virus.
Supplementary Figure 8 Schematic representation of the effect of rs1015164A/G variant on HIV infection.
The rs1015164A/G variant associates with CCR5AS expression, where rs1015164A marks high CCR5AS expression. High CCR5AS expression enhances CCR5 expression post-transcriptionally by sequestering the RNA binding protein Raly, inhibiting the binding of Raly to the CCR5 3’UTR, and protecting CCR5 mRNA from Raly-mediated decay. Higher expression levels of CCR5AS result in increased cell surface expression of the HIV co-receptor CCR5 and higher levels of HIV infection, providing the functional basis for the association between rs1015164A and poor HIV control.
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Kulkarni, S., Lied, A., Kulkarni, V. et al. CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome. Nat Immunol 20, 824–834 (2019). https://doi.org/10.1038/s41590-019-0406-1
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