scholarly journals Noninfectious papilloma virus–like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 1841-1849 ◽  
Author(s):  
J. Mohamad Fakruddin ◽  
Richard A. Lempicki ◽  
Robert J. Gorelick ◽  
Jun Yang ◽  
Joseph W. Adelsberger ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Interleukin 10 ◽  
Hpv Infection ◽  
Interferon Α ◽  
Novel Therapy ◽  
Peripheral Blood Mononuclear ◽  
Papilloma Virus ◽  
Hiv 1

AbstractHuman papilloma virus (HPV)–like particles (VLPs) have been used as a vaccine to prevent HPV infection. Recent studies demonstrate that VLPs bind to dendritic cells and induce the expression of antiviral cytokines such as interferon-α (IFN-α), interleukin-10 (IL-10) and IFN-γ. In the present study, we evaluated the effect of VLPs on HIV-1 replication in peripheral blood mononuclear cells (PBMCs), CD4+ T cells, and macrophages. Here, we show that VLPs suppress the replication of both X4 and R5 HIV-1 without affecting the expression of CD4, CXCR4, and CCR5. Soluble factor(s) released by PBMCs and macrophages on VLPs treatment inhibited HIV-1 replication. To determine the inhibitory factors, DNA microarray analysis was performed using VLP-treated PBMCs and macrophages. VLPs induced the genes associated with IFN induction, immune responses, and antiviral responses, among with the recently described cytokine IL-27. Subsequently, IL-27 was found to be a potent inhibitor of HIV-1 replication in PBMCs, CD4+ T cells, and macrophages. Taken together, our studies identify a novel role of IL-27 in restricting HIV-1 replication and suggest that further examination of the inhibitory property of IL-27 may pave the way for a novel therapy for HIV-1 infection.

Up-regulation of HIV coreceptors CXCR4 and CCR5 on CD4+ T cells during human endotoxemia and after stimulation with (myco)bacterial antigens: the role of cytokines

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2649-2654 ◽  
Author(s):  
Nicole P. Juffermans ◽  
William A. Paxton ◽  
Pascale E. P. Dekkers ◽  
Annelies Verbon ◽  
Evert de Jonge ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Lipoteichoic Acid ◽  
Interleukin 10 ◽  
Virus Infectivity ◽  
Peripheral Blood Mononuclear

Abstract Concurrent infections in patients with human immunodeficiency virus (HIV) infection stimulate HIV replication. Chemokine receptors CXCR4 and CCR5 can act as HIV coreceptors. The authors hypothesized that concurrent infection increases the HIV load through up-regulation of CXCR4 and CCR5. Using experimental endotoxemia as a model of infection, changes in HIV coreceptor expression were assessed in 8 subjects injected with lipopolysaccharide (LPS, 4 ng/kg). The expression of CXCR4 and CCR5 on CD4+ T cells was increased 2- to 4-fold, 4 to 6 hours after LPS injection. In whole blood in vitro, LPS induced a time- and dose-dependent increase in the expression of CXCR4 and CCR5 on CD4+ T cells. Similar changes were observed after stimulation with cell wall components ofMycobacterium tuberculosis (lipoarabinnomannan) orStaphylococcus aureus (lipoteichoic acid), or with staphylococcal enterotoxin B. LPS increased viral infectivity of CD4-enriched peripheral blood mononuclear cells (PBMCs) with a T-tropic HIV strain. In contrast, M-tropic virus infectivity was reduced, possibly because of elevated levels of the CCR5 ligand cytokines RANTES and MIP-1β. LPS-stimulated up-regulation of CXCR4 and CCR5 in vitro was inhibited by anti-TNF and anti-IFNγ. Incubation with recombinant TNF or IFNγ mimicked the LPS effect. Anti–interleukin 10 (anti–IL-10) reduced CCR5 expression, without influencing CXCR4. In accordance, rIL-10 induced up-regulation of CCR5, but not of CXCR4. Intercurrent infections during HIV infection may up-regulate CXCR4 and CCR5 on CD4+ T cells, at least in part via the action of cytokines. Such infections may favor selectivity of HIV for CD4+ T cells expressing CXCR4.

scholarly journals The Inhibition of HIV-1 Entry Imposed by Interferon Inducible Transmembrane Proteins Is Independent of Co-Receptor Usage

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 413 ◽  
Author(s):  
Jingyou Yu ◽  
Shan-Lu Liu
Keyword(s):  
T Cells ◽  
Viral Entry ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Transmembrane Proteins ◽  
Target Cells ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Receptor Usage ◽  
Hiv 1

Interferon inducible transmembrane proteins (IFITMs) are one of several IFN-stimulated genes (ISGs) that restrict entry of enveloped viruses, including flaviviruses, filoviruses and retroviruses. It has been recently reported that in U87 glioblastoma cells IFITM proteins inhibit HIV-1 entry in a co-receptor-dependent manner, that is, IFITM1 is more inhibitory on CCR5 tropic HIV-1 whereas IFITM2/3 confers a greater suppression of CXCR4 counterparts. However, how entry of HIV-1 with distinct co-receptor usage is modulated by different IFITM orthologs in physiologically relevant CD4+ T cells and monocytes/macrophages has not been investigated in detail. Here, we report that overexpression of IFITM1, 2 and 3 in human CD4+ HuT78 cells, SupT1 cells, monocytic THP-1 cells and U87 cells expressing CD4 and co-receptor CCR5 or CXCR4, suppressed entry of CXCR4 tropic viruses NL4.3 and HXB2, CCR5 tropic viruses AD8 and JRFL, dual tropic 89.6 virus, as well as a panel of 32 transmitted founder (T/F) viruses, with a consistent order of potency, that is, IFITM3 > IFITM2 > IFITM1. Consistent with previous reports, we found that some CCR5-using HIV-1 isolates, such as AD8 and JRFL, were relatively resistant to inhibition by IFITM2 and IFITM3, although the effect can be cell-type dependent. However, in no case have we observed that IFITM1 had a stronger inhibition on entry of any HIV-1 strains tested, including those of CCR5-using T/Fs. We knocked down the endogenous IFITMs in peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells and observed that, while this treatment did greatly enhance the multiple-round of HIV-1 replication but had modest effect to rescue the single-round HIV-1 infection, reinforcing our previous conclusion that the predominant effect of IFITMs on HIV-1 infection is in viral producer cells, rather than in target cells to block viral entry. Overall, our results argue against the idea that IFITM proteins distinguish co-receptors CCR5 and CXCR4 to inhibit entry but emphasize that the predominant role of IFITMs on HIV-1 is in producer cells that intrinsically impair the viral infectivity.

Up-regulation of HIV coreceptors CXCR4 and CCR5 on CD4+ T cells during human endotoxemia and after stimulation with (myco)bacterial antigens: the role of cytokines

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2649-2654 ◽  
Author(s):  
Nicole P. Juffermans ◽  
William A. Paxton ◽  
Pascale E. P. Dekkers ◽  
Annelies Verbon ◽  
Evert de Jonge ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Lipoteichoic Acid ◽  
Interleukin 10 ◽  
Virus Infectivity ◽  
Peripheral Blood Mononuclear

Concurrent infections in patients with human immunodeficiency virus (HIV) infection stimulate HIV replication. Chemokine receptors CXCR4 and CCR5 can act as HIV coreceptors. The authors hypothesized that concurrent infection increases the HIV load through up-regulation of CXCR4 and CCR5. Using experimental endotoxemia as a model of infection, changes in HIV coreceptor expression were assessed in 8 subjects injected with lipopolysaccharide (LPS, 4 ng/kg). The expression of CXCR4 and CCR5 on CD4+ T cells was increased 2- to 4-fold, 4 to 6 hours after LPS injection. In whole blood in vitro, LPS induced a time- and dose-dependent increase in the expression of CXCR4 and CCR5 on CD4+ T cells. Similar changes were observed after stimulation with cell wall components ofMycobacterium tuberculosis (lipoarabinnomannan) orStaphylococcus aureus (lipoteichoic acid), or with staphylococcal enterotoxin B. LPS increased viral infectivity of CD4-enriched peripheral blood mononuclear cells (PBMCs) with a T-tropic HIV strain. In contrast, M-tropic virus infectivity was reduced, possibly because of elevated levels of the CCR5 ligand cytokines RANTES and MIP-1β. LPS-stimulated up-regulation of CXCR4 and CCR5 in vitro was inhibited by anti-TNF and anti-IFNγ. Incubation with recombinant TNF or IFNγ mimicked the LPS effect. Anti–interleukin 10 (anti–IL-10) reduced CCR5 expression, without influencing CXCR4. In accordance, rIL-10 induced up-regulation of CCR5, but not of CXCR4. Intercurrent infections during HIV infection may up-regulate CXCR4 and CCR5 on CD4+ T cells, at least in part via the action of cytokines. Such infections may favor selectivity of HIV for CD4+ T cells expressing CXCR4.

scholarly journals OP0033 REGULATORY T CELL CD39 EXPRESSION AS A PREDICTOR OF EARLY REMISSION-INDUCTION WITH METHOTREXATE IN NEW-ONSET RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 18.2-18
Author(s):  
P. Brown ◽  
A. Anderson ◽  
B. Hargreaves ◽  
A. Morgan ◽  
J. D. Isaacs ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Disease Modifying Therapy ◽  
Blood Mononuclear Cells ◽  
Treatment Naïve ◽  
Disease Modifying ◽  
Pre Treatment

Background:The long term outcomes for patients with rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate remains the key first line disease modifying therapy for the majority of patients, with 40% achieving an ACR50 on monotherapy(1). There are at present no effective biomarkers to predict treatment response, preventing effective personalisation of therapy. A putative mechanism of action of methotrexate, the potentiation of anti-inflammatory adenosine signalling, may inform biomarker discovery. By antagonism of the ATIC enzyme in the purine synthesis pathway, methotrexate has been proposed to increase the release of adenosine moieties from cells, which exert an anti-inflammatory effect through interaction with ADORA2 receptors(2). Lower expression of CD39 (a cell surface 5-’ectonucleotidase required for the first step in the conversion of ATP to adenosine) on circulating regulatory T-Lymphocytes (Tregs) was previously identified in patients already established on methotrexate who were not responding (DAS28 >4.0 vs <3.0)(3). We therefore hypothesised that pre-treatment CD39 expression on these cells may have clinical utility as a predictor of early methotrexate efficacy.Objectives:To characterise CD39 expression in peripheral blood mononuclear cells in RA patients naïve to disease modifying therapy commencing methotrexate, and relate this expression to 4 variable DAS28CRP remission (<2.6) at 6 months.Methods:68 treatment naïve early RA patients starting methotrexate were recruited from the Newcastle Early Arthritis Clinic and followed up for 6 months. Serial blood samples were taken before and during methotrexate therapy with peripheral blood mononuclear cells isolated by density centrifugation. Expression of CD39 by major immune subsets (CD4+ and CD8+ T-cells, B-lymphocytes, natural killer cells and monocytes) was determined by flow cytometry. The statistical analysis used was binomial logistic regression with baseline DAS28CRP used as a covariate due to the significant association of baseline disease activity with treatment response.Results:Higher pre-treatment CD39 expression was observed in circulating CD4+ T-cells of patients who subsequently achieved clinical remission at 6 months versus those who did not (median fluorescence 4854.0 vs 3324.2; p = 0.0108; Figure 1-A). This CD39 expression pattern was primarily accounted for by the CD4+CD25 high sub-population (median fluorescence 9804.7 vs 6455.5; p = 0.0065; Figure 1-B). These CD25 high cells were observed to have higher FoxP3 and lower CD127 expression than their CD39 negative counterparts, indicating a Treg phenotype. No significant associations were observed with any other circulating subset. A ROC curve demonstrates the discriminative utility of differential CD39 expression in the CD4+CD25 high population for the prediction of DAS28CRP remission in this cohort, showing greater specificity than sensitivity for remission prediction(AUC: 0.725; 95% CI: 0.53 - 0.92; Figure 1-C). Longitudinally, no significant induction or suppression of the CD39 marker was observed amongst patients who did or did not achieve remission over the 6 months follow-up period.Figure 1.Six month DAS28CRP remission versus pre-treatment median fluorescence of CD39 expression on CD4+ T-cells (A); CD25 High expressing CD4+ T-cells (B); and ROC curve of predictive utility of pre-treatment CD39 expression on CD25 High CD4+ T-cells (C).Conclusion:These findings support the potential role of CD39 in the mechanism of methotrexate response. Expression of CD39 on circulating Tregs in treatment-naïve RA patients may have particular value in identifying early RA patients likely to respond to methotrexate, and hence add value to evolving multi-parameter discriminatory algorithms.References:[1]Hazlewood GS, et al. BMJ. 2016 21;353:i1777[2]Brown PM, et al. Nat Rev Rheumatol. 2016;12(12):731-742[3]Peres RS, et al. Proc Natl Acad Sci U S A. 2015;112(8):2509-2514Disclosure of Interests:None declared

scholarly journals Selection following isolation of human immunodeficiency virus type 1 in peripheral blood mononuclear cells and herpesvirus saimiri-transformed T cells is comparable

2002 ◽  
Vol 83 (6) ◽  
pp. 1343-1352 ◽  
Author(s):  
Natalie N. Zheng ◽  
Cherelyn Vella ◽  
Philippa J. Easterbrook ◽  
Rod S. Daniels
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Herpesvirus Saimiri ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Hiv 1

In attempts to improve isolation rates and virus yields for human immunodeficiency virus (HIV), the use of herpesvirus saimiri-immortalized T cells (HVS T cells) has been investigated as an alternative to/improvement over peripheral blood mononuclear cells (PBMCs). Here we characterize isolates rescued, in the two cell types, from two asymptomatic, long-term non-progressing HIV-1-infected individuals. All rescued viruses replicated in PBMCs and HVS T cells only, displaying a non-syncytium inducing (NSI) phenotype, and using CCR5 as co-receptor. Furthemore, PBMC/HVS T cell virus pairs displayed similar neutralization profiles. Full-length, expression-competent env genes were rescued from all virus isolates and directly from the patient samples using proviral DNA and viral RNA as templates. Compared with the sequences retrieved directly from the patient samples, both cell types showed similar selection characteristics. Whilst the selections were distinct for individual patient samples, they shared a common characteristic in selecting for viruses with increased negative charge across the V2 domain of the viral glycoproteins. The latter was observed at the env gene sequencing level for three other patients whose HIV strains were isolated in PBMCs only. This further supports a common selection for viral sequences that display a macrophage-tropic/NSI phenotype and shows that HVS T cells are a viable alternative to PBMCs for HIV-1 isolation.

scholarly journals Expression Cloning of an Immunodominant Family of Mycobacterium tuberculosis Antigens Using Human Cd4+ T Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 551-560 ◽  
Author(s):  
Mark R. Alderson ◽  
Teresa Bement ◽  
Craig H. Day ◽  
Liqing Zhu ◽  
David Molesh ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Genomic Library ◽  
Cell Epitope ◽  
Single Amino Acid ◽  
Expression Cloning ◽  
Peripheral Blood Mononuclear

Development of a subunit vaccine for Mycobacterium tuberculosis (Mtb) is likely to be dependent on the identification of T cell antigens that induce strong proliferation and interferon γ production from healthy purified protein derivative (PPD)+ donors. We have developed a sensitive and rapid technique for screening an Mtb genomic library expressed in Escherichia coli using Mtb-specific CD4+ T cells. Using this technique, we identified a family of highly related Mtb antigens. The gene of one family member encodes a 9.9-kD antigen, termed Mtb9.9A. Recombinant Mtb9.9A protein, expressed and purified from E. coli, elicited strong T cell proliferation and IFN-γ production by peripheral blood mononuclear cells from PPD+ but not PPD− individuals. Southern blot analysis and examination of the Mtb genome sequence revealed a family of highly related genes. A T cell line from a PPD+ donor that failed to react with recombinant Mtb9.9A recognized one of the other family members, Mtb9.9C. Synthetic peptides were used to map the T cell epitope recognized by this line, and revealed a single amino acid substitution in this region when compared with Mtb9.9A. The direct identification of antigens using T cells from immune donors will undoubtedly be critical for the development of vaccines to several intracellular pathogens.

scholarly journals Defective HIV-1 proviruses produce viral proteins

2020 ◽  
Vol 117 (7) ◽  
pp. 3704-3710 ◽  
Author(s):  
Hiromi Imamichi ◽  
Mindy Smith ◽  
Joseph W. Adelsberger ◽  
Taisuke Izumi ◽  
Francesca Scrimieri ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Viral Proteins ◽  
Open Reading Frames ◽  
Peripheral Blood Mononuclear ◽  
Hiv Rna ◽  
Rna Transcripts ◽  
Extracellular Virus ◽  
Hiv 1

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as “defective” by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant “graveyard” of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell–cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

scholarly journals Donor-Derived CD4+ T Cells and Human Herpesvirus 6B Detection After Allogeneic Hematopoietic Cell Transplantation

2020 ◽  
Author(s):  
Derek J Hanson ◽  
Hu Xie ◽  
Danielle M Zerr ◽  
Wendy M Leisenring ◽  
Keith R Jerome ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cd4 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Peripheral Blood Mononuclear

Abstract We sought to determine whether donor-derived human herpesvirus (HHV) 6B–specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell transplantation. We identified 33 patients who received HLA-matched, non–T-cell–depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B–specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B–specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation.

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