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Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages [1]

['Michiko Shimoda', 'Department Of Dermatology', 'School Of Medicine', 'University Of California', 'Davis', 'Sacramento', 'California', 'United States Of America', 'Uc Davis Comprehensive Cancer Center', 'Tomoki Inagaki']

Date: 2023-12

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14 + monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.

Kaposi’s sarcoma-associated virus (KSHV) is the causative agent of highly inflammatory diseases that include Kaposi’s sarcoma and KSHV-inflammatory cytokine syndrome (KICS). Macrophages are important immune cells that regulate inflammation by stimulating both innate and adaptive immune systems. A small fraction of monocytes differentiates into macrophages to acquire a longer life span and migrate to residential areas. Deregulation of macrophage functions weakens host immune defense mechanisms, allowing secondary infections resulting in prolonged inflammation. Here, we demonstrate that KSHV infection to monocytes facilitates their transition into macrophages; however, those infected macrophages have impaired immune stimulatory function. Such tradition depends on the expression of KSHV vIL-6, a virally encoded IL-6 homolog. Prolonged vIL-6 stimulation in culture also induced a similar phenotype in monocytes. These results suggest that continuous stimulation by KSHV-derived vIL-6 deregulates host macrophage functions. This mechanism may be associated with hyperinflammatory phenotypes seen in KSHV-associated diseases.

Data Availability: The scRNA-seq and RNA-seq data underlying Figs 1 and 4 are openly available at GEO NCBI under accession number GSE227167. The data underlying Fig 2 are available in https://doi.org/10.6084/m9.figshare.22273279 . All other relevant date are in the manuscript and its supporting information files.

KSHV-encoded viral interleukin-6 (vIL-6) is a homolog of human interleukin-6, which is encoded by KSHV ORF-K2 and is highly expressed during the lytic replication cycle [ 15 ]. Viral IL-6 is also expressed at physiologically functional levels in latently infected cells [ 16 ] and is detectable in the sera and/or tumor tissues of patients with KS, PEL, and MCD [ 17 ]. Viral IL-6 enhances cell proliferation, endothelial cell migration, and angiogenesis, leading to tumorigenesis, and has been suggested to be a driver of KICS [ 18 , 19 ]. In addition, vIL-6 transgenic mice developed IL-6-dependent MCD-like disease [ 20 ] and supported tumor metastasis in a murine xenograft model [ 21 ]. Mechanistically, vIL-6 directly binds to the gp130 subunit of the IL-6 receptor without the need for the IL-6 receptor α, and actives the JAK/STAT pathway to induce STAT3 phosphorylation and acetylation [ 8 , 22 , 23 ]. In addition, vIL-6 activates the AKT pathway to promote numerous oncogenic phenotypes [ 18 , 19 , 24 , 25 ]. STAT3 activation by vIL-6 also increases the VEGF expression through the downregulating caveolin 1 [ 8 ] and promotes angiogenesis, suggesting that vIL-6 plays an important role in tumorigenesis through STAT activation. Given that the prototypical human IL-6 plays a critical role in immune regulation and inflammation, vIL-6 is thought to play a pivotal role in inflammatory KSHV diseases. Here, we reveal the role of vIL-6 in the regulation of monocytes by utilizing recombinant KSHV and de novo infection to the peripheral blood mononuclear cells.

Natural transmission of KSHV most likely occurs through salivary and sexual transmission or during transplantation of KSHV-positive organs into a naïve recipient, although initial KSHV infection is typically asymptomatic [ 2 , 9 ]. In experimental settings, KSHV has been shown to infect various types of cell lines and primary cells, such as epithelial cells and immune cells that include B cells, monocytes, and dendritic cells through binding to specific cell surface receptors such as Siglec DC-SIGN [ 10 – 14 ]. However, it remains unclear as to whether KSHV may strategically infect a particular cell type among PBMC. The mechanisms by which KSHV facilitates a lifelong infection by increasing viral reservoirs and impacts the host immune system are also not entirely clear.

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV), or human gamma herpesvirus 8 (HHV-8), is an oncogenic double-stranded DNA virus that establishes a lifelong latent infection [ 2 ]. KSHV is the etiologic agent of Kaposi’s sarcoma and is associated with two lymphoproliferative disorders: multicentric Castleman’s disease (MCD) and HIV-associated primary effusion lymphoma (PEL). KSHV-inflammatory cytokine syndrome (KICS) may also represent a prodromic form of KSHV-MCD, which exhibits elevated KSHV viral loads and circulating inflammatory cytokines including IL-6, IL-10, and a KSHV-encoded IL-6 homolog (vIL-6) [ 3 – 8 ]. These highly inflammatory diseases are devastating and a leading cause of cancer deaths in people living with HIV. Therefore, understanding the mechanism of KSHV infection and its association with inflammatory disease development is crucial for finding a cure for these diseases.

A virus is an infectious agent that can only replicate within a living host organism. Because of this dependence, viruses have evolved mechanisms to exploit normal cell functions to escape host immune surveillance for their survival advantage. This exploitation is sometimes associated with prolonged damage to the host, leading to pathologic processes and diseases caused by the viral infection [ 1 ].

Results and discussion

KSHV preferentially infects CD14+ monocytes among PBMC, triggering an inflammatory response and macrophage differentiation To study cell type-specific KSHV infection, we employed a single cell (sc)RNA-seq analysis approach. Recombinant KSHV (rKSHV.219) virions were purified by two serial ultracentrifugations from the culture supernatant of the iSLK.219 cell line, an inducible recombinant KSHV producer cell. Peripheral blood mononuclear cells (PBMCs) were infected with rKSHV.219 at MOI = 1, fixed at various time points (day 0, 1, 2, and 4) after infection, and subjected to scRNA-seq analysis. KSHV infection and lytic replication in single cells were then monitored by the expression of all KSHV genes. As shown in Fig 1A, unsupervised Uniform Manifold Approximation and Projection (UMAP) for dimension reduction analysis identified 9 clusters among peripheral blood mononuclear cells (PBMCs). The detailed list of differentially expressed genes for each cluster is shown in S1 Table. Each of the clusters was then associated with known immune cell subsets based on corresponding lineage-specific gene expression. Thus, KLRD1(CD94), CD14, APOBEC3A, VMO1, CD79A, and CD3E genes were used as guiding markers for the classification of NK cells, monocytes, intermediate monocytes, non-classical monocytes, B cells, and T cells, respectively, based on the immune cell data available from the Human Protein Atlas [26] (S1A Fig). All four types of immune cells were present during 4-day infection period, and monocyte cell population was slightly decreased at day 4. (S1B Fig). PPT PowerPoint slide

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TIFF original image Download: Fig 1. KSHV preferentially infects monocytes and triggers the monocyte inflammatory transcription program. PBMCs were infected with rKSV.219 at MOI = 1, fixed at various time points (pre-infection, day 1, 2, and 4) after infection, and subjected to 10x Genomics Chromium scRNA-seq analysis. (A) UMAP visualizes 9 PBMC clusters (CL1: Classical Monocytes, CL2: Intermediate Monocytes, CL3 and CL4: NK cell subset, CL5: T cell subset, CL6: B cells, CL7: Non Classical Monocytes, CL8: IFN-responsive cells, and CL9: CD8 enriched T cell subset) in a 1 day-post-infection (dpi) sample based on lineage-specific gene expression of KLRD1, CD14, APOBEC3A, VMO1, CD79A, and CD3E genes for NK cells, monocytes, intermediate monocytes, non-classical monocytes, B cells, and T cells, respectively. The detailed list of differentially expressed genes for each cluster is shown in S1 Table. (B) KSHV-encoded K2 (vIL-6) and ORF16 (vBCL2) expression overlapped with CD14 expression at 1 dpi. (C) The kinetic scRNA-seq analysis on pre-infection, 1 dpi, 2 dpi, and 4 dpi revealed that the colocalized expression of KSHV-encoded K2 and ORF16 and the monocyte-related genes CD14, IL3RA (CD123), CD68, and IL6ST (gp130). (D) KSHV infection in CD14+ monocytes triggered the activation and inflammatory response at 1 dpi with the upregulation of CD86, CD80, TNFα, CCL2, IL1b, and IL6. (E) KSHV infection in CD14+ monocytes later upregulated the expression of genes associated with differentiation of M2-like macrophages with suppressive phenotype (MRC1, CD163, IL10, RNASE1, C1QA, and TREM2). Gene expression levels are indicated by heatmap bars. A representative of three similar experiments is shown. https://doi.org/10.1371/journal.ppat.1011703.g001 As shown in Fig 1B, de novo KSHV infection of PBMCs in conjunction with scRNA-seq analysis at 1-day post-infection (dpi) revealed that K2 (vIL-6) and ORF16 (vBCL2) had the two most sequence reads detected among all the KSHV open reading frames (S2A Fig). These KSHV reads were almost entirely overlapped with CD14 expression. It should be noted that scant K2 expression was also found in CD79A+ B cells, KLRD1+ NK, and CD3E+ T cell clusters (Figs 1B and S2). KSHV has been shown to establish latent infection in B cells, causing B-cell lymphoma [2]. However, the correlation in expression of CD14 and K2 was highly significant (p = 8 x 10−191) compared to that of CD19 and K2 (p = 0.065) at 1 dpi. The following kinetic scRNA-seq analysis showed that the expression of both K2 and ORF16 and the host gene expression associated with monocytes such as CD14, IL3RA(CD123), and CD68, as well as IL6ST (gp130), the receptor of vIL-6 [8,22,23], was colocalized during 1 to 4 dpi (Fig 1C). Using eGFP reporter gene expression under human EF-1 promoter in rKSHV.219-infected cells, we confirmed that eGFP-positive cells mainly express CD14, HLA-DR, and CD11c but not lineage markers for B cells (CD19) or T cells (CD3), and that ∼70% of CD14+ cells were eGFP-positive (S3 Fig). By intracellular staining of vIL-6 at 2 dpi, we also confirmed that the majority (>80%) of CD14+ monocytes expressed high levels of vIL-6 protein whereas ∼50% of non-CD14+ lymphocytes were weakly stained with antibody against vIL-6 (S4 Fig). In this experiment, the culture medium was not replenished during the period. Infectious KSHV virions that remained in the culture or were newly released from infected cells could have infected other cell subsets of PBMC besides CD14+ monocytes. Based on these results, we concluded that KSHV preferentially infects CD14+ monocytes and that monocytes can support KSHV lytic replication along with vIL-6 protein expression. The kinetic scRNA-seq analysis also revealed that KSHV infection in CD14+ monocytes triggered the activation and inflammatory response immediately after KSHV infection at 1 dpi as evidenced by the upregulation of CD86, CD80, TNFα, CCL2, IL1β, and IL6 (Fig 1D). The latter was followed by the expression of genes associated with differentiation of M2-like and Tumor-associated macrophages with a suppressive phenotype (MRC1, CD163, IL10, RNASE1, C1QA, and TREM2) [27–29] during 2–4 dpi (Fig 1E). Collectively, scRNA-seq analysis demonstrates that KSHV infection triggers a monocyte inflammatory response followed by a macrophage differentiation program.

KSHV infection promotes activation and proliferation of CD14+ monocytes in a manner dependent on vIL-6 To further study the biological significance of vIL-6 expression and STAT 1 and 3 activations, monocytes were isolated from PBMCs (n = 6) using a magnetic beads-based negative enrichment method and infected with vIL-6STOP or vIL-6REV KSHV (MOI = 1). The viability and phenotype were then analyzed by flow cytometry at 2 dpi. KSHV infection increases CD274 (PD-L1) expression in human monocytes [31]. We found that total cell viability (Fig 3A) and the frequency of activated PD-L1+ cells (Fig 3B and 3C) were significantly increased by KSHV infection regardless of the expression of vIL-6. These results were expected based on the CyTOF signaling analysis results that demonstrate that the initial host response against vIL-6REV and vIL-6STOP infection was indistinguishable. The results were also supported by the observation that KSHV infection promptly induced inflammatory cytokine expression in monocytes (Fig 1D). Inflammatory cytokines such as TNFα produced by activated monocytes can support their survival in an autocrine manner during the inflammatory response [32]. Therefore, it is possible that the effect of vIL-6 on cell survival, if any, could be overridden by the effect of other inflammatory cytokines during the early host anti-viral response against KSHV. PPT PowerPoint slide

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TIFF original image Download: Fig 3. KSHV preferentially infects and expands CD14+ monocytes with an inflammatory response in a manner dependent on vIL-6. Monocytes were isolated negatively from PBMCs (n = 6) using magnetic beads-based negative enrichment and infected with vIL-6STOP or vIL-6REV rKSHV (MOI = 1). (A) The frequencies of live cells at 2 dpi by live/dead staining are shown. (B) Representative FACS profiles of infected monocytes analyzed by flow cytometry for Ki67, CD16, and PD-L1 expressing cells. (C) The frequencies for Ki67+, CD16+, and PD-L1+ cells are shown. Data represent two similar experiments. (D) Representative images of cell blasts in the indicated treatment conditions (x100). (E) Representative FACS profiles of each sample for pSTAT1 and pSTAT3 intracellular staining with the percentage of gated pSTAT1- and pSTAT3- expressing cells are shown. Data represent two similar experiments. p values shown are by ANOVA with a paired comparison with Tukey’s multiple comparison test. p < 0.05: statistically significant. https://doi.org/10.1371/journal.ppat.1011703.g003 On the other hand, the frequency of Ki67+ proliferating cells and that of CD16+ cells were significantly increased in a manner dependent on the presence of vIL-6 (Fig 3B and 3C). Consistent with flow cytometry analyses, larger and more frequent proliferating blast cells were observed in response to vIL-6REV infection compared to that of vIL-6STOP infection (Fig 3D). Intracellular staining of monocytes also confirmed that the frequency of pSTAT1 and pSTAT3 in monocytes continued to be higher in vIL-6REV-infection compared to that in vIL-6STOP or mock-infection at 2 dpi (Fig 3E), suggesting that vIL-6 expression is required for sustaining STAT activation. These results collectively suggest that vIL-6 expression during the early KSHV infection increases the proliferation of infected monocytes via STAT 1 and 3 activation. The cellular environment in monocytes may have a unique role in sustaining STAT activation with KSHV infection.

KSHV infection changes the transcriptional landscape of macrophages in a manner dependent on vIL-6 expression To reveal the biological effect of vIL-6 expression in infected monocytes, we next conducted a transcriptomic analysis of de novo infected monocytes. To this end, total RNA was isolated from monocytes harvested 7 days post KSHV infection, and RNA-seq was performed (Fig 4A in the Left panel). By 7 dpi, the recovery of vIL-6REV-infected monocytes was higher than vIL-6STOP-infected monocytes, as shown later in Fig 5A, and they are consistent with increased Ki67+ expression (Fig 3B and 3C). Principal component analysis (PCA) demonstrated markedly distinct transcriptional profiles between vIL-6REV-infected and vIL-6STOP-infected monocytes (Fig 4A). Volcano plots depict the higher numbers of differentially regulated genes in vIL-6REV-infected monocytes (Fig 4B, e.g., relative to PBS control). To our surprise, vIL-6STOP infection had little impact on the transcriptional landscape of monocytes at 7 dpi, suggesting that sustaining STAT signaling activation may be important for cell reprogramming or vIL-6 is important for KSHV reactivation or maintaining persistent KSHV lytic replication. The phenotype is partly seen in reactivated iSLK cells ([30] and S5D Fig). Those two functions of vIL-6 are likely to be mutually exclusive. PPT PowerPoint slide

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TIFF original image Download: Fig 4. Differential gene expression analysis between wild-type KSHV and vIL-6STOP KSHV infected monocytes. (A) A schematic illustration of the KSHV infection experiment (Left). Monocytes were infected with vIL-6REV, vIL-6STOP, or mock-infected (PBS). At 7 dpi, cells were harvested for RNA-seq analysis (n = 2/group). Principal component analysis (PCA) of RNA-seq data from independent biological replicates is shown (Right). The number in parenthesis indicates the percentage of total variance explained by each PC. Colored dots represent individual samples infected with mock (PBS-treated), vIL-6REV, and vIL-6STOP. (B) Volcano plots for differentially expressed genes (log2 FC threshold = 1, p-value threshold = 0.05) between vIL-6REV and vIL-6STOP (Top), vIL-6 REV and mock (Middle) and vIL-6STOP and mock (Bottom). The log2 FC indicates the mean expression for each. The functional enrichment analysis of upregulated genes (C) and downregulated genes (D) in vIL-6REV- compared to vIL-6STOP-infected monocytes. DAVID functional enrichment analysis was performed, and the analysis results of the top 5 enriched pathways are shown (Right). The representative results of Gene Set Enrichment Analysis (GSEA) are shown (Left). (E) Heatmap of representative genes from enriched gene sets for upregulated IFN-inducible genes (C) or downregulated MHC-II genes (D) in vIL-6REV- compared to vIL-6STOP-infected monocytes. (F) Putative transcription factors that are responsible for differentially expressed genes between vIL-6 REV and vIL-6 STOP KSHV infection. The bar charts indicate p values for enrichment. The following parameters were used; Organism: Homo sapiens (hg38), Experiment type: ChiP (TFs and others), Cell type Class: Blood, and Threshold for significance: 50. https://doi.org/10.1371/journal.ppat.1011703.g004 Among the genes differentially expressed between vIL-6REV and vIL-6STOP infection, interferon-induced genes, such as IFITM2 and IFITM3, are substantially upregulated in response to vIL-6REV infection (Fig 4B, Top panel). Consistently, Gene Set Enrichment Analysis (GSEA) also revealed that genes associated with host anti-viral innate responses were enriched in vIL-6REV infection (Figs 4C and S7A), while the pathways involving in antigen processing and presentation were significantly downregulated in vIL-6REV but not in vIL-6STOP infected monocytes (Figs 4D and S7B). While we expected to see upregulation of IFN-related genes in KSHV infected cells, down-regulation of MHC class II genes were unexpected. Representative upregulated IFN-inducible genes and down-regulation of MHC-II genes were visualized in the heatmap (Fig 4E). To identify the putative transcription factors that are responsible for vIL-6-driven gene regulation, we utilized bioinformatics tools to examine transcription factors whose binding are enriched on promoter regions of differentially transcribed genes. As shown in Fig 4F, interferon regulatory factors STAT1 and STAT2 were found to be putative transcription factors responsible for driving vIL-6-associated phenotypes. In support of this, we found that a subsets of STAT target genes were expressed slightly higher in vIL-6REV-infected monocytes compared to vIL-6STOP-infected monocytes (S7C Fig).

KSHV infection generates macrophages with an immunosuppressive phenotype in a manner dependent on vIL-6 expression Following the transcriptomic study that demonstrated transcriptional landscape changes in KSHV-infected macrophages, we next examined biological effects on monocytes after KSHV de novo infection on 7–14 dpi. For this, we compared the T-cell activation function between vIL-6REV and vIL-6STOP infected monocytes. We showed in Fig 1E that the M2-like or suppressive macrophage differentiation program were triggered by 4 dpi. Consistent with this, monocytes in cultures showed features indicative of macrophages, such as being predominantly of large cellularity with higher FSC and SSC with HLA-DR and CD16 expression (Fig 5A). Consistent with the transcriptomic analysis in Fig 4D, the macrophages derived from vIL-6REV infection (vIL-6REV) expressed lower levels of HLA-DR compared to control groups (Fig 5B). To test the direct effect of vIL-6 in such phenotypic changes (absence of other viral genes), we generated functional recombinant vIL-6 protein, which is capable of activating STAT1 and 3 (S8 Fig). Monocytes were cultured in the presence of vIL-6 (200 ng/ml in serum-free medium) for 9 days, and the phenotype was analyzed by flow cytometry. As shown in Fig 5C, the overall monocyte viability was increased from 20% to 59% in the presence of vIL-6. In addition, monocytes recovered from the 9-day culture showed a trend of reduced HLA-DR expression (Fig 5D) compared to monocytes cultured without vIL-6 (PBS). The results suggested that vIL-6 treatment alone could induce phenotypic changes similar to vIL-6REV infection, perhaps due to continued STAT activations. PPT PowerPoint slide

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TIFF original image Download: Fig 5. KSHV infection promotes macrophage differentiation with an immunosuppressive phenotype in a manner dependent on vIL-6 expression. Monocytes were infected with vIL-6REV or vIL-6STOP (MOI = 1), uninfected (PBS) and cultured for 7–14 days, or treated with vIL-6 (200 ng/ml in serum-free medium) for 9 days. Each sample was analyzed by flow cytometry with isotype control staining as a control. (A) The average frequency of macrophages in each culture (n = 3) is based on representative FSC-H and SSC-H profiles for uninfected (PBS) and vIL-6REV- and vIL-6STOP-infected samples. The macrophage gate was further analyzed for HLA-DR and CD16 expression to confirm typical macrophage phenotype. A representative overlay for the treated sample with unstained control (blue) and stained with antibodies for HLA-DR and CD16 (red). Data combine four independent experiments with different donor samples. Dots represent the average % of biological replicates (n = 2–3). (B) The average geometric mean fluorescent intensity (MFI) of HLA-DR for each macrophage sample with representative overlays is shown. Data combine four independent experiments with different donor samples. Dots represent the average HLA-DR gMFI of biological replicates (n = 2–3). (C) Representative FACS plots of live monocytes one week after vIL-6 treatment and the average frequencies (n = 3) are shown. (D) The average gMFI of HLA-DR for each macrophage sample in (C) with representative overlays are shown. Data represent two similar experiments. (E) An experimental design of T cell proliferation assay with macrophages (Top) and representative histograms of T cells (gated based on FSC-A and SSC-A) for CSFE are shown. T cells without or with anti-CD3/CD28 tetramer stimulation are used as controls. (F) The average frequencies of the CFSE-negative population determined as in (E) for each sample are shown (n = 3). p values shown are by ANOVA with a paired comparison with Tukey’s multiple comparison test. p < 0.05: statistically significant. Data represent two similar experiments. https://doi.org/10.1371/journal.ppat.1011703.g005 Finally, to evaluate T cell co-stimulatory capacity, CSFE-labeled allogeneic T cells were cultured with macrophages derived from monocytes mock-infected or infected with vIL-6REV or vIL-6STOP. T cell proliferation was then evaluated as CSFE-dilution by flow cytometry (Fig 5E, Top panel) in the presence or absence of anti-CD3 stimulation and with the T cell culture with anti-CD3/CD28 tetramer stimulation as a positive control. As shown in Fig 5E and summarized in Fig 5F, vIL-6REV infection significantly impaired T-cell activation function of infected macrophage, which is demonstrated by the decreasing CFSE-negative proliferated T cells in co-culture to (18.5%) compared with uninfected (50.8%) or vIL-6STOP-infection groups (78.6%) in the presence of anti-CD3 stimulation. Similar results were found in the cultures without anti-CD3 stimulation, with the exception that the extent of T cell proliferation was smaller. These observations are consistent with the transcriptional analysis in Fig 4, which collectively demonstrates that sustained vIL-6-driven host anti-viral response in infected monocytes induces an immune suppressive phenotype in differentiating macrophages.

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