Bone marrow stromal cell antigen 2 (BST-2) restricts mouse mammary tumor virus (MMTV) replication in vivo
© Jones et al; licensee BioMed Central Ltd. 2012
Received: 20 October 2011
Accepted: 27 January 2012
Published: 27 January 2012
Bone marrow stromal cell antigen 2 (BST-2) is a cellular factor that restricts the egress of viruses such as human immunodeficiency virus (HIV-1) from the surface of infected cells, preventing infection of new cells. BST-2 is variably expressed in most cell types, and its expression is enhanced by cytokines such as type I interferon alpha (IFN-α). In this present study, we used the beta-retrovirus, mouse mammary tumor virus (MMTV) as a model to examine the role of mouse BST-2 in host infection in vivo.
By using RNA interference, we show that loss of BST-2 enhances MMTV replication in cultured mammary tumor cells and in vivo. In cultured cells, BST-2 inhibits virus accumulation in the culture medium, and co-localizes at the cell surface with virus structural proteins. Furthermore, both scanning electron micrograph (SEM) and transmission electron micrograph (TEM) show that MMTV accumulates on the surface of IFNα-stimulated cells.
Our data provide evidence that BST-2 restricts MMTV release from naturally infected cells and that BST-2 is an antiviral factor in vivo.
KeywordsBST-2 Tetherin Interferon alpha MMTV In vivo SEM TEM
Bone marrow stromal cell antigen 2 (BST-2) protein also known as tetherin/CD317 is a potent restriction factor against a wide range of enveloped viruses such as HIV, FIV, KSHV, MMTV, SIV, Lassa, Marbug, Ebola, and MLV [1–5]. BST-2 achieves its anti-viral effect by connecting both viral and host cell membranes, thus preventing virus egress [6–9]. While BST-2 inhibits virus release, most viruses including HIV-1, HIV-2, and Ebola virus have developed strategies to antagonize BST-2 by degradation, down-regulation of expression, or reduction of its steady-state level [1, 2, 7, 10–14]. In addition to inhibiting virus egress and virus replication in cell culture, there is evidence that, following interferon-induction, BST-2 is up-regulated and incorporated into budding virions [2, 6, 8, 9]. While the antiviral activity of BST-2 has been demonstrated in tissue culture cells, there has been no evidence that BST-2 exerts antiviral activity in vivo. In this context, we evaluated the ability of mouse BST-2 to restrict the replication of the exogenous murine retrovirus mouse mammary tumor virus (MMTV) in cell culture and in mice.
In vivo, MMTV first infects antigen presenting cells (APCs) such as B cells and dendritic cells (DCs) at the site of infection [15–19]. MMTV infected APCs present virus-encoded superantigen (Sag) to T cells expressing Sag-specific T-cell receptor (TCR) Vβ chains. This immunological synapse causes stimulation of Sag-reactive T cells and proliferation of lymphocytes thereby promoting virus replication. Both lymphoid and myeloid cells infected with MMTV are capable of producing infectious virus  and infected lymphoid cells are necessary for virus spread and mammary carcinogenesis [20, 21].
Although MMTV infects and causes mammary cancer in infected mice; nonetheless, infected cells do not produce high virus titer, and time to MMTV-induced cancer is rather long, suggesting that virus replication and spread may be restricted by host factors like BST-2. Indeed, we demonstrate that BST-2 co-localizes with MMTV Gag and Env, and inhibits MMTV particle release in tissue culture cells. Importantly, MMTV infection of mice was significantly inhibited by BST-2.
IFNα induces BST-2 expression and restricts MMTV release
Next, we examined whether BST-2 is responsible for IFNα-dependent inhibition of MMTV release. GR cells stably silenced for BST-2 expression with a lentiviral construct carrying BST-2 specific shRNA or control shRNA were stimulated with IFNα or vehicle. Culture supernatants were collected 24 hours later and subjected to Western blot analysis for MMTV capsid protein p27. The corresponding cells were examined for BST-2 protein (Figure 1G). Results show that while shRNA was able to silence BST-2 and enhance accumulation of viral particles in culture supernatant (Figure 1H), IFNα stimulation of shRNA cells results in increased cell surface BST-2 protein expression (Figure 1G) and a reduction in the amount of viral particles accumulated in the culture supernatant (Figure 1H). This result shows that the reduction in the amount of extracellular viral particles observed in IFNα treated cells is linked to BST-2 induction.
IFNα causes accumulation of MMTV structures at the cell surface
BST-2 co-localizes with MMTV structural proteins at the cell surface
Depletion of endogenous BST-2 enhances MMTV particle release and replication in cell culture
Overexpression of BST-2 inhibits MMTV replication
BST-2 specific siRNA depleted endogenous BST-2 in murine lymph nodes
siRNA mediated silencing of endogenous BST-2 enhances MMTV replication and spread in vivo
Local administration of BST-2 siRNA mediates BST-2 depletion in vivo (Figures 6B and 6C). To determine the role of endogenous BST-2 in virus replication in vivo, we administered either a control siRNA, or siRNA that targets BST-2 mRNA to mice, followed by infection with MMTV. Virus replication was significantly higher in siRNA treated mice compared to their siControl or no siRNA counterparts (Figure 6D). In addition, we observed significantly higher virus load in the spleens of mice that received siRNA (Figure 6E). These data show for the first time that siRNA is capable of mediating BST-2 knock down in vivo (Figures 6B and 6C); and that loss of BST-2 in the draining lymph node for the site of initial infection results in higher rate of virus replication and dissemination in vivo (Figures 6D and 6E).
Here, we describe an important anti-viral function for BST-2 in the mouse. Many in vitro and ex vivo studies have shown that BST-2 inhibits the replication of a number of viruses [1–9]. By using MMTV, we directly demonstrate that BST-2 plays a role in virus replication in vivo. Administration of siRNA sequences into mouse footpad results in knock-down of endogenous lymph node BST-2. This assay allowed us to demonstrate that BST-2 functions as a virus restriction factor in a natural host organism. We chose to silence lymph node BST-2 because lymphocytes play a critical role in the in vivo infection with MMTV and other retroviruses such as HIV-1; and in the absence of a knockout model, siRNA provides the best alternative. The significantly higher virus load observed in BST-2 silenced lymph nodes implies that loss of BST-2 enhances virus replication.
BST-2 expression inhibits the egress of HIV-1, HIV-2, Ebola, Marburg and MLV; and we found that it also inhibits the accumulation of MMTV particles in the culture medium. The inhibitory effect of BST-2 on accumulation of extracellular MMTV particles in culture supernatant is consistent with the effect of BST-2 on virus release from the cell surface as has been observed for other viruses [1–5]. The observation that BST-2 co-localizes with MMTV Env and Gag further suggests that BST-2 prevents the accumulation of MMTV particles in culture supernatants. Our EM data support previously documented studies that MMTV buds off from the plasma membrane and microvilli . The cell surface visualization by SEM provides an opportunity to demonstrate that induction of BST-2 with IFNα facilitates accumulation of MMTV on the cell surface. This finding was backed by our protein analyses showing that stimulation of MMTV producer cells with IFNα results in less accumulation of MMTV particles in the culture supernatant.
We have directly demonstrated in this study that loss of BST-2 enhances replication of MMTV in vivo. However, it remains to be determined why mice become infected with MMTV in the presence of the endogenous BST-2. It is worth noting that MMTV has co-existed with mice for over 20 million years  and perhaps must have evolved to avoid most hosts' anti-viral defense mechanisms. The findings of this study are important as it has shown that BST-2 function as anti-viral in the host. Based on this report, we are now focused on using MMTV as a model to understand the role of BST-2 in viral pathogenesis.
Materials and methods
All experiments involving mice were performed in accordance to NIH guidelines, the Animal Welfare Act, and US federal law. The experiments approved by the University of Iowa Animal Care and Use Committee (IACUC). Mice were housed according to the policies of the Institutional Animal Care and Use Committee of the University of Iowa.
BST-2 plasmids used in the study were previously described  and kindly provided by Dr. Paul Bates, University of Pennsylvania, Philadelphia, PA. The MMTV env (Q61) construct , MMTV molecular clone HYB PRO (HP) , and the rat glucocorticoid receptor (RSVGR)  were kindly provided by Dr. Susan Ross, University of Pennsylvania, Philadelphia, PA.
C57BL/6 and C3H/HeN mice were purchased from the Jackson Laboratory and National Cancer Institute (NCI) respectively.
NMuMG (derived from normal mammary tissue of a Namru mouse strain), GR (a mammary carcinoma cell line), Mm5MT (a mammary carcinoma cell line from C3H/HeN mouse strain), 3T3 MEF and 293T cell lines were purchased from American Type Culture Collection (ATCC). TRH3 cells are 293T-mTfR1 (293T cells that stably express MMTV entry receptor transferrin receptor 1 [mTfr1]) and have been previously described . TRH3-BST-2 and TRH3-Vector cells (TRH3 cells stably expressing BST-2 or empty vector). CGRES6-GFP cells (feline kidney stably transfected with a GFP-tagged MMTV proviral construct  was obtained from Dr. Susan Ross of the university of Pennsylvania. All cells were maintained according to the suppliers' instructions. Both GR and Mm5MT cells are from MMTV-induced mammary tumor and both produce infectious MMTV particles.
Generation of TRH3 cell-line stably expressing mBST-2
To generate a TRH3-BST2 stable cell line, we co-transfected 6 μg of BST-2 and 1 μg of puromycin (selection marker) plasmids into TRH3 cells using polyethylenimine (PEI) transfection reagent. Following overnight incubation, transfection medium was changed, and replaced with medium containing puromycin dihydrochloride (3 μg/ml, Santa Cruz Biotechnology, Inc.). The cells were left in culture with three changes of medium to remove dead cells. By day 10 after transfection, several individual clones of stably transfected cells emerged and clones were picked and expanded. Level of BST-2 expression was examined by FACs analysis. After examination, clones with the highest BST-2 expression were expanded and some cells frozen or used for experiments.
Antibodies, siRNAs, shRNAs, and other reagents
Antibodies used in this study includes goat anti-gp52 (Env) and anti-p27 (capsid) previously described [32, 33]. Others are unconjugated rat anti-mouse BST-2 clone 129c, Alexa flour 647 conjugated anti-mouse BST-2 clone 129c , and FITC conjugated anti-mouse BST-2 clone 927 purchased from eBioscience. Rabbit anti-BST-2 and mouse anti-tubulin were from Abnova and Li-core respectively. The following isotype control antibodies were used: Rat IgG2a and Rat IgG2b, both from eBiosciences. The following secondary antibodies from Li-core were used: RDye 680 donkey anti-mouse, IRDye 680 LT conjugated donkey anti-rabbit, IRDye 800CW donkey anti-goat, and IRDye 800CW conjugated goat anti-rabbit. Rabbit anti-rat Alexa Fluor 594 and chicken anti-goat Alexa Fluor 488 were from Invitrogen. The in vivo ready silencer Select target specific siRNA, control siRNA, and SiPort NeoFX transfection reagent were from Ambion while plasmids for target-specific Mission shRNA, control shRNA, and polybrene were obtained from Sigma. BST-2 shRNA and control shRNA lentiviral particles were produced from plasmids of target-specific Mission shRNA and control shRNA by the University of Iowa Vector Core Facility. Recombinant mouse interferon alpha (IFN-α) was from Miltenyi Biotech. Vector-shield was from Vector Laboratories and Lipofectamine 2000 was from Invitrogen.
Infection of mice
In vivo infection of mice was performed with 50 μl of MMTV.MM5MT inoculated subcutaneously on the hind footpad. At different times after infection, mice were sacrificed and the popliteal lymph node draining the site of infection from each mouse was harvested. Lymphocytes were obtained and used for fluorescence-activated cell-sorting (FACS) analysis or used for DNA and RNA extraction.
BST-2 knockdown by shRNA and siRNA in cell culture
BST-2 shRNA lentiviral particles containing 3 target-specific constructs and shRNA constructs encoding a scrambled sequence (Santa Cruz Biotechnology, Santa Cruz, CA) or target specific Mission shRNA and a corresponding control shRNA (Sigma) were used to knock down BST-2 gene expression. Briefly, mouse mammary epithelial tumor cell line GR were transduced with control or BST-2 shRNA lentiviral particles at a ratio of 5 infectious units of virus per cell in the presence of 8 μg/mL polybrene. The next day, fresh media was added to cells and incubated for another 24 hours. In some experiments, puromycin at 2 μg/ml was added to the culture medium for the selection of cells that had stably incorporated shRNA. BST-2 gene silencing was confirmed at the mRNA and protein levels by qPCR and FACS. Knockdown of BST-2 by siRNA was achieved using Ambion's in vivo ready silencer Select target specific or siRNA in vivo ready scrambled siRNA. Briefly, 250 pico moles of siRNA sequences were mixed with Lipofectamine 2000 following manufacturer's recommendation and used to transfect NMuMG, GR or MEFs. The next day, fresh medium was added to cells and incubated until assayed for BST-2 and MMTV mRNA. NMuMG and MEFs were passaged and used for detection of BST-2 and virus replication experiments. Experiments were repeated at least 3 times with similar results.
Western blots of virus preparations, cell lysates from MMTV infected cells, cells transiently transfected with env and capsid plasmids, or immuno-precipitates of protein complexes were probed with anti-total MMTV, anti-gp52, and anti-p27. The species-appropriate IRDye secondary antibodies were used, followed by detection with the Odyssey Infrared Imaging System (LI-COR Biosciences).
DNA, RNA isolation and real-time quantitative PCR (qPCR)
Immuno-fluorescence and confocal microscopy
293T cells were co-transfected with plasmids expressing BST-2, rat glucocorticoid receptor (RSVGR) and MMTV proviral genome (HP) using lipofectamine 2000. The next day cells were treated with DEX and 24 hours later fixed in 4% paraformaldehyde in PBS for 10 minutes. Cells were then washed once with PBS and incubated for 3 hours in IF buffer (0.5% Triton X-100, 0.5%, sodium deoxycholate, 1% bovine serum albumin, 0.05% sodium azide in PSB). Primary antibodies were diluted in IF buffer as follows: rat anti-BST-2 (1:100), goat anti-p27 (1:100) or goat anti-gp52 (1:100) and detected with rabbit anti-rat Alexa Fluor 594 and chicken anti-goat Alexa Fluor 488. All secondary autobodies were dilated 1:1000 in IF buffer. All confocal microscopy images were taken with Zeiss 510 confocal microscope.
Approximately, 1 × 106 GR, MM5MT, NMuMG, 3T3 MEF, 293T, and lymphocytes were stained in PBS + 1% bovine serum albumin (Sigma-Aldrich) for 30 min on ice with Alexa flour 647 anti-mouse BST-2 (clone 129c) or FITC anti-mouse BST-2 (clone 927) and APC anti-mouse IgG2b. Cells were extensively washed in PBS, fixed with 2% paraformaldehyde and subjected to FACS. At least ten-thousand events were collected for each sample using FACS calibur flow cytometer (BD). Cellular frequency and mean fluorescence intensity (MFI) were determined by Flowjo analysis software (TreeStar).
Virus release assay
GR cells were induced for virus production with 1 μM of dexamethasone (DEX)  and treated with IFNα or vehicle for 24 hours. Culture supernatants from cells were clarified by low speed centrifugation, passed through a 0.45 μm filter, and virions were pelleted through a 20% sucrose layer at 32,000g as previously described (30-31). Pellets of virus particles and corresponding cell extracts were denatured and analyzed by SDS-PAGE and Western blot assays. In some experiments, virus particles were used for qPCR analysis of viral RNA or to infect TRH3 cells.
Statistical analysis of significant differences between experimental groups was tested using paired two-tailed Student's t test, and a p value of 0.05 was considered significant. Error bars represent standard deviations.
*Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States of America.
List of abbreviations
bone marrow stromal cell antigen 2
human immunodeficiency virus type 1
human immunodeficiency virus type 2
interferon alpha and beta, siRNA: short interfering RNA
short hair pin RNA
normal murine mammary gland
simian immunodeficiency virus
scanning electron micrograph
transmission electron micrograph.
We are also grateful to Dr. Peter Pfeffer of AgResearch Crown Research Institute, New Zealand for the puromycin primer sequence. This research was supported by University of Iowa Startup funds to CMO. PHJ was partly supported by University of Iowa Startup funds to CMO and Immunology T32 training grant to the University of Iowa. This publication was made possible through core services from the University of Iowa Vector core and Central Microscopy Research Facility.
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