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A Role for microRNA-155 Modulation in the Anti-HIV-1 Effects of Toll-Like Receptor 3 Stimulation in Macrophages

Swaminathan, Gokul, Rossi, Fiorella, Sierra, Luz-Jeannette, Gupta, Archana, Navas-Martín, Sonia, Martín-García, Julio·2012·PLoS Pathogens
DOI 10.1371/journal.ppat.1002937PMC PMC3447756
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Figure 1 TLR3 and TLR4 stimulation abrogates susceptibility to HIV-1 infection of primary macrophages. (A) MDMs were untreated or incubated for 16 h with specific ligands for TLR3 (10 µg/ml poly(I∶C)), TLR4 (10 µg/ml LPS), TLR7 (5 µg/ml Imiquimod) or TLR9 (10 µg/ml CpG), and, after washing, infected with a fully-infectious, luciferase-reporter recombinant virus containing the macrophage-tropic ADA envelope glycoprotein. Inocula were removed after 4–6 h and cells were maintained for 5–6 days before quantitating infection through luciferase (luc) activity in cell lysates. Results with cells from four normal donors are shown as relative infection compared to untreated (mean ± standard deviation [SD]). (B) MDMs were untreated or incubated overnight with specific ligands for TLR2 (108 PFU/ml heat-killed Listeria monocytogenes, HKLM), TLR3, TLR4, TLR7 or TLR9 (as indicated above), and then infected with luc-reporter, lentiviral particles pseudotyped with the macrophage-tropic BaL or BR HIV-1 envelope glycoproteins, or with VSV-G. Luc activity was measured 2–3 days post-infection and results from a representative experiment are shown as actual luc activity in cell lysates measured as relative light units per second (mean ± SD).
Figure 1 TLR3 and TLR4 stimulation abrogates susceptibility to HIV-1 infection of primary macrophages. (A) MDMs were untreated or incubated for 16 h with specific ligands for TLR3 (10 µg/ml poly(I∶C)), TLR4 (10 µg/ml LPS), TLR7 (5 µg/ml Imiquimod) or TLR9 (10 µg/ml CpG), and, after washing, infected with a fully-infectious, luciferase-reporter recombinant virus containing the macrophage-tropic ADA envelope glycoprotein. Inocula were removed after 4–6 h and cells were maintained for 5–6 days before quantitating infection through luciferase (luc) activity in cell lysates. Results with cells from four normal donors are shown as relative infection compared to untreated (mean ± standard deviation [SD]). (B) MDMs were untreated or incubated overnight with specific ligands for TLR2 (108 PFU/ml heat-killed Listeria monocytogenes, HKLM), TLR3, TLR4, TLR7 or TLR9 (as indicated above), and then infected with luc-reporter, lentiviral particles pseudotyped with the macrophage-tropic BaL or BR HIV-1 envelope glycoproteins, or with VSV-G. Luc activity was measured 2–3 days post-infection and results from a representative experiment are shown as actual luc activity in cell lysates measured as relative light units per second (mean ± SD).CC BY · PubMed Central
Figure 2 Production of type I IFNs, pro-inflammatory cytokines and β-chemokines after TLR stimulation in macrophages. MDMs were cultured in quadruplicate for 16 h unstimulated or with the ligands for TLR2, TLR3, TLR4, TLR7 or TLR9, and then supernatants were collected, clarified, aliquoted and stored at −80°C until use. Commercial enzyme-linked immunoassays were used for quantitation of type I IFNs IFNα (PBL InterferonSource and Thermo Scientific) (A) and IFNβ (Thermo Scientific) (B), pro-inflammatory cytokines TNF-α (C) and IL-6 (D) (both from eBioscience), and β-chemokines MIP-1α (CCL3) (E) (SABiosciences), MIP-1β (CCL4) (F) (Mabtech) and RANTES (CCL5) (G) (Peprotech). All samples were analyzed in duplicate. Multiple donors are shown for type I IFNs and one representative donor is shown for pro-inflammatory cytokines and β-chemokines. Results are shown as mean ± SD of duplicate cultures. Dashed lines indicate the limit of detection of the assays for quantitation of type I IFNs.
Figure 2 Production of type I IFNs, pro-inflammatory cytokines and β-chemokines after TLR stimulation in macrophages. MDMs were cultured in quadruplicate for 16 h unstimulated or with the ligands for TLR2, TLR3, TLR4, TLR7 or TLR9, and then supernatants were collected, clarified, aliquoted and stored at −80°C until use. Commercial enzyme-linked immunoassays were used for quantitation of type I IFNs IFNα (PBL InterferonSource and Thermo Scientific) (A) and IFNβ (Thermo Scientific) (B), pro-inflammatory cytokines TNF-α (C) and IL-6 (D) (both from eBioscience), and β-chemokines MIP-1α (CCL3) (E) (SABiosciences), MIP-1β (CCL4) (F) (Mabtech) and RANTES (CCL5) (G) (Peprotech). All samples were analyzed in duplicate. Multiple donors are shown for type I IFNs and one representative donor is shown for pro-inflammatory cytokines and β-chemokines. Results are shown as mean ± SD of duplicate cultures. Dashed lines indicate the limit of detection of the assays for quantitation of type I IFNs.CC BY · PubMed Central
Figure 3 Stimulation through TLR3 and TLR4, but not TLR7, increases miR-155 levels in primary macrophages. MDMs from 12 different donors were cultured for 16 h unstimulated or with the ligands for TLR3, TLR4 or TLR7, and then used for infection with BaL pseudotypes (A) or for RNA isolation with Trizol (Invitrogen) for miR-155 quantitation (B). Infection was evaluated in 8 replicates as percent luc activity compared to unstimulated MDMs (mean ± SD). Relative miR-155 levels were evaluated in duplicate in total RNA using TaqMan miRNA Reverse Transcription kit and Universal PCR Master Mix, and the miR-155-specific TaqMan miRNA Assay (Applied Biosystems), and results were calculated relative to the U6 snRNA levels using the comparative Ct method (also referred to as the 2−ΔΔCt method), and expressed as fold-change (mean ± SD) with respect to the unstimulated control. ND, not determined.
Figure 3 Stimulation through TLR3 and TLR4, but not TLR7, increases miR-155 levels in primary macrophages. MDMs from 12 different donors were cultured for 16 h unstimulated or with the ligands for TLR3, TLR4 or TLR7, and then used for infection with BaL pseudotypes (A) or for RNA isolation with Trizol (Invitrogen) for miR-155 quantitation (B). Infection was evaluated in 8 replicates as percent luc activity compared to unstimulated MDMs (mean ± SD). Relative miR-155 levels were evaluated in duplicate in total RNA using TaqMan miRNA Reverse Transcription kit and Universal PCR Master Mix, and the miR-155-specific TaqMan miRNA Assay (Applied Biosystems), and results were calculated relative to the U6 snRNA levels using the comparative Ct method (also referred to as the 2−ΔΔCt method), and expressed as fold-change (mean ± SD) with respect to the unstimulated control. ND, not determined.CC BY · PubMed Central
Figure 4 Inhibition of miR-155 in TLR3-stimulated macrophages increases their susceptibility to HIV-1 infection. MDMs from seven different donors were transfected for 24 h (LipoRNAiMax, Invitrogen) with 30 nM anti-miR-155 antagomir or a scrambled control that doesn't target any known human miRNA (anti-miR-scr) (Applied Biosystems), and then stimulated with poly(I∶C) (A and B) or Imiquimod (C and D) for 16 h, before either infecting with BaL pseudotypes (A, C) or isolating RNA for miR-155 quantitation (B, D). Infection was evaluated in 8 replicates as percent luc activity compared to untreated, unstimulated MDMs (mean ± SD). Relative miR-155 levels were evaluated as in Figure 3 and results are shown as fold-change (mean ± SD) with respect to the untreated, unstimulated MDMs.
Figure 4 Inhibition of miR-155 in TLR3-stimulated macrophages increases their susceptibility to HIV-1 infection. MDMs from seven different donors were transfected for 24 h (LipoRNAiMax, Invitrogen) with 30 nM anti-miR-155 antagomir or a scrambled control that doesn't target any known human miRNA (anti-miR-scr) (Applied Biosystems), and then stimulated with poly(I∶C) (A and B) or Imiquimod (C and D) for 16 h, before either infecting with BaL pseudotypes (A, C) or isolating RNA for miR-155 quantitation (B, D). Infection was evaluated in 8 replicates as percent luc activity compared to untreated, unstimulated MDMs (mean ± SD). Relative miR-155 levels were evaluated as in Figure 3 and results are shown as fold-change (mean ± SD) with respect to the untreated, unstimulated MDMs.CC BY · PubMed Central
Figure 5 miR-155 over-expression in primary macrophages and cell lines decreases their susceptibility to HIV-1 infection. MDMs from 12 different donors were transfected with miR-155 expression plasmid (pEZX-miR-155) or scrambled control (pEZX-scrambled) (GeneCopoeia) using jetPEI-Macrophage transfection reagent (Polyplus), following manufacturer's instructions. After 48 h., cells were either infected with BaL pseudotype (A) to evaluate infection through luciferase activity as indicated above; or total RNA was isolated for miR-155 quantitation by real-time PCR (B) as indicated above. HOS-CD4-CCR5 cells were also transfected with various amounts of the miR-155 or scrambled plasmids using calcium precipitation, and then used for infection with BaL or VSV-G pseudotypes (C) or RNA isolation for miR-155 quantitation (D). Infection was evaluated in 8 replicates as percent luc activity compared to untransfected cells (mean ± SD). Relative miR-155 levels were evaluated as in Figure 3 and results are shown as fold-change (mean ± SD) with respect to the untransfected control.
Figure 5 miR-155 over-expression in primary macrophages and cell lines decreases their susceptibility to HIV-1 infection. MDMs from 12 different donors were transfected with miR-155 expression plasmid (pEZX-miR-155) or scrambled control (pEZX-scrambled) (GeneCopoeia) using jetPEI-Macrophage transfection reagent (Polyplus), following manufacturer's instructions. After 48 h., cells were either infected with BaL pseudotype (A) to evaluate infection through luciferase activity as indicated above; or total RNA was isolated for miR-155 quantitation by real-time PCR (B) as indicated above. HOS-CD4-CCR5 cells were also transfected with various amounts of the miR-155 or scrambled plasmids using calcium precipitation, and then used for infection with BaL or VSV-G pseudotypes (C) or RNA isolation for miR-155 quantitation (D). Infection was evaluated in 8 replicates as percent luc activity compared to untransfected cells (mean ± SD). Relative miR-155 levels were evaluated as in Figure 3 and results are shown as fold-change (mean ± SD) with respect to the untransfected control.CC BY · PubMed Central
Figure 6 Increase in miR-155 leads to late RT products accumulation and greatly reduced integration. Total DNA was isolated at 48 h post-infection from: (i) BaL pseudotype-infected MDMs (from three different donors) that were unstimulated, or stimulated with poly(I∶C), LPS or Imiquimod, and in the case of poly(I∶C), untransfected or transfected (prior to stimulation) with anti-miR-155 or anti-miR-scr (A–C); (ii) BaL pseudotype-infected MDMs (from three different donors) that were untransfected or transfected (prior to infection) with miR-155 expression plasmid (pEZX-miR-155) or scrambled control (pEZX-scrambled) (D–F). Real-time PCR was performed in total DNA for the absolute quantitation of early RT product (RU5) (A,D), late RT product (U5Ψ) (B,E) and integrated pro-virus (C,F), as described in Materials and Methods. Copy numbers per cell were calculated using PBGD as endogenous control to normalize for DNA recovery and number of cells, and are shown as mean ± SD from two independent quantitations. Arrows indicate lack of amplification in real-time PCR, implying levels below the limit of detection of the technique.
Figure 6 Increase in miR-155 leads to late RT products accumulation and greatly reduced integration. Total DNA was isolated at 48 h post-infection from: (i) BaL pseudotype-infected MDMs (from three different donors) that were unstimulated, or stimulated with poly(I∶C), LPS or Imiquimod, and in the case of poly(I∶C), untransfected or transfected (prior to stimulation) with anti-miR-155 or anti-miR-scr (A–C); (ii) BaL pseudotype-infected MDMs (from three different donors) that were untransfected or transfected (prior to infection) with miR-155 expression plasmid (pEZX-miR-155) or scrambled control (pEZX-scrambled) (D–F). Real-time PCR was performed in total DNA for the absolute quantitation of early RT product (RU5) (A,D), late RT product (U5Ψ) (B,E) and integrated pro-virus (C,F), as described in Materials and Methods. Copy numbers per cell were calculated using PBGD as endogenous control to normalize for DNA recovery and number of cells, and are shown as mean ± SD from two independent quantitations. Arrows indicate lack of amplification in real-time PCR, implying levels below the limit of detection of the technique.CC BY · PubMed Central
Figure 7 Increased miR-155 levels result in reduced mRNA levels of several HIV-1 dependency factors. We isolated total RNA at: (i) 48 h post-transfection of MDMs from five different donors with either pEZX-miR-155 or pEZX-scrambled control (A); and (ii) 24 h post-stimulation of MDMs from two different donors with poly(I∶C) or LPS (B); and then performed relative quantitation of mRNAs by real-time RT-PCR of two experimentally-demonstrated miR-155 targets (SHIP1 and SOCS1), and four not previously described, potential miR-155 targets (ADAM10, TNPO3, LEDGF and Nup153), using TaqMan Gene Expression assays (Applied Biosystems). Results were calculated using 18S rRNA as internal control and the comparative Ct method (also known as the 2−ΔΔCt method), and are shown as fold-change (mean ± SD from two independent quantitations) with respect to the untransfected control in (A), or as fold-change (calculated from a single experiment) with respect to unstimulated in (B).
Figure 7 Increased miR-155 levels result in reduced mRNA levels of several HIV-1 dependency factors. We isolated total RNA at: (i) 48 h post-transfection of MDMs from five different donors with either pEZX-miR-155 or pEZX-scrambled control (A); and (ii) 24 h post-stimulation of MDMs from two different donors with poly(I∶C) or LPS (B); and then performed relative quantitation of mRNAs by real-time RT-PCR of two experimentally-demonstrated miR-155 targets (SHIP1 and SOCS1), and four not previously described, potential miR-155 targets (ADAM10, TNPO3, LEDGF and Nup153), using TaqMan Gene Expression assays (Applied Biosystems). Results were calculated using 18S rRNA as internal control and the comparative Ct method (also known as the 2−ΔΔCt method), and are shown as fold-change (mean ± SD from two independent quantitations) with respect to the untransfected control in (A), or as fold-change (calculated from a single experiment) with respect to unstimulated in (B).CC BY · PubMed Central
Figure 8 The 3′UTRs of LEDGF, ADAM10, TNPO3 and Nup153 are targeted by miR-155. 293T cells were co-transfected by calcium precipitation with: (i) pEZX-miR-155 or the pEZX-scrambled control; and (ii) with miTarget microRNA 3′UTR Target Sequence (pEZX-MT01) expression clones (GeneCopoeia), which contain the 3′UTR sequence of interest (LEDGF, ADAM10, TNPO3, Nup153 and a negative control 3′UTR) inserted downstream of the firefly luciferase, and an independently-controlled Renilla luciferase gene to be used as normalization control, allowing functional validation of predicted miRNA targets. At 48 h post-co-transfection of 293T cells, cells were lysed and the regulatory effect of miR-155 on its potential target was assessed in cell lysates with a dual luciferase assay. Results were calculated as [(firefly/Renilla)miR-155/(firefly/Renilla)scrambled]×100, for each of the pEZX-MT01 clones, and are expressed as mean ± SD from four independent wells.
Figure 8 The 3′UTRs of LEDGF, ADAM10, TNPO3 and Nup153 are targeted by miR-155. 293T cells were co-transfected by calcium precipitation with: (i) pEZX-miR-155 or the pEZX-scrambled control; and (ii) with miTarget microRNA 3′UTR Target Sequence (pEZX-MT01) expression clones (GeneCopoeia), which contain the 3′UTR sequence of interest (LEDGF, ADAM10, TNPO3, Nup153 and a negative control 3′UTR) inserted downstream of the firefly luciferase, and an independently-controlled Renilla luciferase gene to be used as normalization control, allowing functional validation of predicted miRNA targets. At 48 h post-co-transfection of 293T cells, cells were lysed and the regulatory effect of miR-155 on its potential target was assessed in cell lysates with a dual luciferase assay. Results were calculated as [(firefly/Renilla)miR-155/(firefly/Renilla)scrambled]×100, for each of the pEZX-MT01 clones, and are expressed as mean ± SD from four independent wells.CC BY · PubMed Central
Figure 9 Increased miR-155 levels result in reduced protein levels of several HIV-1 dependency factors. We generated cellular lysates at: (i) 48 h post-stimulation of MDMs from three different donors with poly(I∶C) or LPS (A,B); and (ii) 48 h post-transfection of MDMs from five different donors with either pEZX-miR-155 or pEZX-scrambled control (C,D); and then performed western-blots using antibodies for ADAM10, LEDGF, Nup153 and TNPO3 (Abcam), and GAPDH (Cell Signaling) as loading control. Intensity of the chemoluminiscent signals was quantitated by densitometry analysis and normalized with the loading control, and is expressed as percent with respect to unstimulated (A,B) or untransfected (C,D) controls. (A) Poly(I∶C) and LPS decreased the levels of ADAM10, LEDGF, Nup153 and TNPO3 (not shown) to a different extent and with some donor-to-donor variation. (B) Effects of poly(I∶C) and LPS on expression of HDFs in MDMs from three donors, expressed as mean ± SD. (C) Ectopic expression of miR-155 led to decreased levels of ADAM10, LEDGF and Nup153, but not TNPO3 (not shown), with some donor-to-donor variation; three out of a total five donors are shown. (D) Effects of ectopic expression of miR-155 on expression of HDFs in MDMs from five donors, expressed as mean ± SD.
Figure 9 Increased miR-155 levels result in reduced protein levels of several HIV-1 dependency factors. We generated cellular lysates at: (i) 48 h post-stimulation of MDMs from three different donors with poly(I∶C) or LPS (A,B); and (ii) 48 h post-transfection of MDMs from five different donors with either pEZX-miR-155 or pEZX-scrambled control (C,D); and then performed western-blots using antibodies for ADAM10, LEDGF, Nup153 and TNPO3 (Abcam), and GAPDH (Cell Signaling) as loading control. Intensity of the chemoluminiscent signals was quantitated by densitometry analysis and normalized with the loading control, and is expressed as percent with respect to unstimulated (A,B) or untransfected (C,D) controls. (A) Poly(I∶C) and LPS decreased the levels of ADAM10, LEDGF, Nup153 and TNPO3 (not shown) to a different extent and with some donor-to-donor variation. (B) Effects of poly(I∶C) and LPS on expression of HDFs in MDMs from three donors, expressed as mean ± SD. (C) Ectopic expression of miR-155 led to decreased levels of ADAM10, LEDGF and Nup153, but not TNPO3 (not shown), with some donor-to-donor variation; three out of a total five donors are shown. (D) Effects of ectopic expression of miR-155 on expression of HDFs in MDMs from five donors, expressed as mean ± SD.CC BY · PubMed Central
Figure 10 Silencing of selected HDFs replicate the miR-155-induced effects. MDMs from one donor were either untransfected or transfected for 48 h (LipoRNAiMax, Invitrogen) with Silencer Negative Control #2 siRNA (which has no significant sequence similarity to human gene sequences and is validated for use in human cells), or with Silencer Select siRNAs (two per target) for LEDGF, ADAM10 and Nup153 (all from Ambion), alone or in various combinations. Subsequently, cells were either lysed for western-blot analyses of protein levels (A) (as in Figure 9), or infected and lysed for quantitation of infection by luciferase activity (B), or infected and lysed for DNA isolation and quantitation of early (C) and late (D) viral RT products and integrated pro-virus (E) (as in Figure 6). Arrows indicate lack of amplification in real-time PCR, implying levels below the limit of detection of the technique.
Figure 10 Silencing of selected HDFs replicate the miR-155-induced effects. MDMs from one donor were either untransfected or transfected for 48 h (LipoRNAiMax, Invitrogen) with Silencer Negative Control #2 siRNA (which has no significant sequence similarity to human gene sequences and is validated for use in human cells), or with Silencer Select siRNAs (two per target) for LEDGF, ADAM10 and Nup153 (all from Ambion), alone or in various combinations. Subsequently, cells were either lysed for western-blot analyses of protein levels (A) (as in Figure 9), or infected and lysed for quantitation of infection by luciferase activity (B), or infected and lysed for DNA isolation and quantitation of early (C) and late (D) viral RT products and integrated pro-virus (E) (as in Figure 6). Arrows indicate lack of amplification in real-time PCR, implying levels below the limit of detection of the technique.CC BY · PubMed Central
Figure 11 Schematic representation of potential miR-155 effects on HIV-1 dependency factors (HDFs). We found that increased levels of miR-155 are induced in macrophages by TLR3 and TLR4 stimulation, and that at least in the case of TLR3, miR-155 contributes to the induced anti-HIV-1 effect. In addition, increased levels of miR-155 in MDMs lead to consistent decreases in the mRNA and protein levels of ADAM10, TNPO3, Nup153 and LEDGF/p75 (PSIP1), which are all HDFs known to participate in trafficking and/or nuclear import of pre-integration complexes (PICs) during HIV-1 infection. These findings, together with our results on the accumulation of late reverse transcription products and the absence or large reduction of integrated pro-viruses and 2-LTR circles in cells expressing increased miR-155 levels, lead us to hypothesize that it is possible a model in which a miR-155 action upon expression of multiple targets, rather than a single one, might generate a cellular environment that is less conducive to HIV-1 infection and thus mediate the anti-HIV-1 effects of miR-155.
Figure 11 Schematic representation of potential miR-155 effects on HIV-1 dependency factors (HDFs). We found that increased levels of miR-155 are induced in macrophages by TLR3 and TLR4 stimulation, and that at least in the case of TLR3, miR-155 contributes to the induced anti-HIV-1 effect. In addition, increased levels of miR-155 in MDMs lead to consistent decreases in the mRNA and protein levels of ADAM10, TNPO3, Nup153 and LEDGF/p75 (PSIP1), which are all HDFs known to participate in trafficking and/or nuclear import of pre-integration complexes (PICs) during HIV-1 infection. These findings, together with our results on the accumulation of late reverse transcription products and the absence or large reduction of integrated pro-viruses and 2-LTR circles in cells expressing increased miR-155 levels, lead us to hypothesize that it is possible a model in which a miR-155 action upon expression of multiple targets, rather than a single one, might generate a cellular environment that is less conducive to HIV-1 infection and thus mediate the anti-HIV-1 effects of miR-155.CC BY · PubMed Central

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Metadata

Authors
Swaminathan, G., Rossi, F., Sierra, L.-J., Gupta, A., Navas-Martín, S., & Martín-García, J.
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2012-09-20
Volume
8
Issue
9
Pages
e1002937
ISSN
1553-7374
DOI
10.1371/journal.ppat.1002937
PMC
PMC3447756
Cited by
103
References
10
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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