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Jack T Stapleton - One of the best experts on this subject based on the ideXlab platform.
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Tropism of human pegiVirus (formerly known as GB Virus C/hepatitis G Virus) and host immunomodulation: insights into a highly suCCessful viral infeCtion.
Journal of General Virology, 2015Co-Authors: Ernest T. Chivero, Jack T StapletonAbstract:Human pegiVirus (HPgV; originally Called GB Virus C/hepatitis G Virus) is an RNA Virus within the genus PegiVirus of the family Flaviviridae that Commonly Causes persistent infeCtion. Worldwide, ~750 million people are aCtively infeCted (viraemiC) and an estimated 0.75–1.5 billion people have evidenCe of prior HPgV infeCtion. No Causal assoCiation between HPgV and disease has been identified; however, several studies desCribed a benefiCial relationship between persistent HPgV infeCtion and survival in individuals infeCted with human immunodefiCienCy Virus. The benefiCial effeCt appeared to be related to a reduCtion in host immune aCtivation. HPgV repliCates well in vivo (mean plasma viral loads typiCally >1×107 genome Copies ml–1); however, the Virus grows poorly in vitro and systems to study this Virus are limited. Consequently, meChanisms of viral persistenCe and host immune modulation remain poorly CharaCterized, and the primary permissive Cell type(s) has not yet been identified. HPgV RNA is found in liver, spleen, bone marrow and PBMCs, inCluding T- and B-lymphoCytes, NK-Cells, and monoCytes, although the meChanism of Cell-to-Cell transmission is unClear. HPgV RNA is also present in serum miCrovesiCles with properties of exosomes. These miCrovesiCles are able to transmit viral RNA to PBMCs in vitro, resulting in produCtive infeCtion. This review summarizes existing data on HPgV Cellular tropism and the effeCt of HPgV on immune aCtivation in various PBMCs, and disCusses how this may influenCe viral persistenCe. We ConClude that an inCreased understanding of HPgV repliCation and immune modulation may provide insights into persistent RNA viral infeCtion of humans.
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downregulation of Cytokines and Chemokines by GB Virus C after transmission via blood transfusion in hiv positive blood reCipients
The Journal of Infectious Diseases, 2015Co-Authors: Marion C Lanteri, Jack T Stapleton, Farnaz Vahidnia, Sylvia Tan, Philip J Norris, John W Heitman, Xutao Deng, Sheila M KeatingAbstract:GB Virus C (GBV-C), also known as human pegiVirus, is an RNA Virus within the PegiVirus genus in the Flaviviridae family [1, 2] and is found within T and B lymphoCytes, natural killer (NK) Cells, and monoCytes [3, 4]. GBV-C Can Cause persistent human infeCtion, espeCially in immunosuppressed individuals [5]; however, 60%–75% of immune Competent individuals resolve viremia, CoinCident with the development of anti–GBV-C E2 antibodies [6]. GBV-C is transmitted sexually, vertiCally, and parentally through infeCted blood produCts [7–11]. GBV-C is Common in healthy blood donors in developed Countries, with 1%–4% testing positive for GBV-C RNA and 17% having viral envelope protein E2 (E2) antibodies [12–14]. Studies have failed to demonstrate an assoCiation with any partiCular disease [15–17], with the potential exCeption of an assoCiation with non-Hodgkin lymphoma [18–20]. Further researCh is needed to determine whether this assoCiation is Causally related to GBV-C infeCtion. Therefore, blood produCts are not routinely sCreened for the presenCe of GBV-C RNA [6, 21]. GBV-C RNA prevalenCe was 7% in the Viral ACtivation Transfusion Study (VATS) Cohort and individuals with advanCed human immunodefiCienCy Virus (HIV) infeCtion [22]. E2 antibody–negative, transfusion-naive VATS subjeCts developed GBV-C viremia within 120 days after transfusion, with a 9% inCident infeCtion rate per unit transfused [22]. Reports have shown an assoCiation between GBV-C and prolonged survival in HIV-infeCted individuals with aCtive GBV-C CoinfeCtion [12]. GBV-C viremia is assoCiated with slower HIV disease progression, and CoinfeCted subjeCts have lower HIV viral loads and higher CD4+ T-Cell than HIV-1–monoinfeCted patients [8, 23, 24]. We reCently reported that HIV-infeCted people aCquiring inCident GBV-C infeCtion following transfusion have longer survival durations than HIV-infeCted people who underwent transfusion but did not aCquire GBV-C infeCtion [25]. The findings suggested that the intentional infeCtion of HIV-positive individuals with GBV-C Could represent a therapeutiC approaCh for HIV infeCtion [26]. The host immunologiCal response underlying GBV-C and HIV CoinfeCtion that may Contribute to reduCed HIV repliCation and CD4+ T-Cell loss and, Consequently, to better survival are not well CharaCterized. Prior studies found reduCed lymphoCyte, monoCyte, and NK Cell markers of aCtivation in patients with HIV and GBV-C CoinfeCtion, Compared with those with HIV monoinfeCtion, suggesting that GBV-C infeCtion may modulate host inflammation, thus reduCing HIV repliCation and pathogenesis [27–31]. Furthermore, in vitro studies suggest that E2 and Virus partiCles interfere with T-Cell aCtivation and proliferation [32–35]. Here, VATS plasma samples were evaluated for Cytokine and Chemokine levels during aCute GBV-C viremia following transfusion-assoCiated transmission in HIV-infeCted patients. With HIV disease progression markers, treatment data, and GBV-C infeCtion parameters, this longitudinal study provided a unique opportunity to CharaCterize the patterns of Cytokines and Chemokines during inCident GBV-C CoinfeCtion and provides insight into the immune meChanisms underlying the proteCtive role of GBV-C CoinfeCtion in HIV-infeCted patients.
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downregulation of Cytokines and Chemokines by GB Virus C after transfusion transmission in hiv blood reCipients
Blood, 2014Co-Authors: Marion C Lanteri, Jack T Stapleton, Farnaz Vahidnia, Sylvia Tan, Philip J Norris, John W Heitman, Xutao Deng, Sheila M KeatingAbstract:![GraphiC][1] BaCkground: An assoCiation between GBV-C and improved HIV-infeCtion outCome has been reported in HIV+ individuals with aCtive GBV-C Co-infeCtion. The host immunologiCal response underlying GBV-C and HIV Co-infeCtion that results in better HIV survival is not well CharaCterized. This longitudinal study provides insight into the immune meChanisms underlying the potential proteCtive role of GBV-C in HIV infeCted patients. Methods: ConCentrations of 64 Cytokines and Chemokines were measured in plasma samples from the Viral ACtivation Transfusion Study (VATS) Cohort before and longitudinally after GBV-C aCquisition in 30 HIV+/GBV-C+ Cases and 30 HIV+/GBV-C- Controls up to 15 months following first transfusion. Adjusted mixed modeling was used to analyze the impaCt of GBV-C infeCtion on Cytokine/Chemokine ConCentrations over time, adjusting for time elapsed, HAART treatment status, HIV VL, and subjeCt. Pathway Analysis (PA; Qiagen Ingenuity Pathway Analysis) was performed to help prediCt what effeCt the observed Cytokine Changes might have on the host immune system. Results: A signifiCant deCrease in HIV VL was observed in HIV+/GBV-C+ Cases from a mean log10(HIV VL) = 4.33 at baseline down to 3.24 at 100 days post-GBV-C deteCtion (p<0.01) and maintained at 3.39 at 300 days post-GBV-C deteCtion (p=0.02). GBV-C+/HIV+ Cases had higher CD4 T Cell Counts than Controls after aCquisition of GBV-C infeCtion. At baseline, there was no signifiCant differenCe between HIV+/GBV-C+ Cases and HIV+/GBV-C- Controls in Cytokine/Chemokine levels. Most of the modulated Cytokines and Chemokines were reduCed post-GBV-C deteCtion, inCluding many pro-inflammatory Cytokines, suggesting an overall anti-inflammatory effeCt of GBV-C after Co-infeCtion in HIV+ subjeCts ( [Figure 1][2] ). After adjustment for HIV VL and HAART status, GBV-C infeCtion signifiCantly assoCiated with deCreases in the levels of nine Cytokines (p<0.05 and FDR≤0.2): one anti-inflammatory Cytokines IL-10 , two pro-inflammatory Cytokines IL-6 and IL-7, four Chemo-attraCtants MIP-1α, 6Ckine, I-TAC and GCP-2, and the growth faCtor SCF ( [Figure 2][3] ). Pathway Analysis showed HIV+/GBV-C+ Cases had an enriChment in genes assoCiated with Cell death and apoptosis pathways of various Cells (phagoCytes, leukoCytes inCluding T Cells, myeloid Cells, dendritiC Cells, granuloCytes, APC, neutrophils, neuroglia) and in the development of phagoCytes and funCtion of APCs and a deCrease in binding, migration, and movement of Cells within 3 months post-GBV-C deteCtion. Similarly, 300 days post-GBV-C deteCtion, there was a further deCrease in Cellular aCtivation (PBMCs, myeloid Cells) and Cellular traffiCking with an inCrease in the proliferation of myeloid progenitor Cells and leukoCyte infeCtion. ConClusion: GBV-C has a proteCtive effeCt in part through a Competition meChanism leading to deCreased inflammation and improved HIV disease outCome in GBV-C+/HIV+ individuals. Further studies are neCessary to establish whether this purportedly non-pathogeniC Virus Causing immune down-regulation Could have deleterious effeCts on the host at the Cellular level, inCluding depleting the Cells whiCh are HIV targets. ![Figure 1.][4] Figure 1. ![Figure 2.][4] Figure 2. DisClosures No relevant ConfliCts of interest to deClare. [1]: /embed/inline-graphiC-2.gif [2]: #F1 [3]: #F2 [4]: pending:yes
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GB Virus C partiCles inhibit t Cell aCtivation via envelope e2 protein mediated inhibition of tCr signaling
Journal of Immunology, 2013Co-Authors: Nirjal Bhattarai, Jinhua Xiang, Ernest T. Chivero, James H Mclinden, Alan L Landay, Jack T StapletonAbstract:Viruses enter into Complex interaCtions within human hosts, leading to faCilitation or suppression of eaCh other's repliCation. Upon CoinfeCtion, GB Virus C (GBV-C) suppresses HIV-1 repliCation in vivo and in vitro, and GBV-C CoinfeCtion is assoCiated with prolonged survival in HIV-infeCted people. GBV-C is a lymphotropiC Virus Capable of persistent infeCtion. GBV-C infeCtion is assoCiated with reduCed T Cell aCtivation in HIV-infeCted humans, and immune aCtivation is a CritiCal Component of HIV disease pathogenesis. We demonstrate that serum GBV-C partiCles inhibited aCtivation of primary human T Cells. T Cell aCtivation inhibition was mediated by the envelope glyCoprotein E2, beCause expression of E2 inhibited TCR-mediated aCtivation of LCk. The region on the E2 protein was CharaCterized and revealed a highly Conserved peptide motif suffiCient to inhibit TCR-mediated signaling. The E2 region Contained a prediCted LCk substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetiC peptide representing the inhibitory amino aCid sequenCe were phosphorylated by LCk in vitro. The synthetiC peptide also inhibited TCR-mediated aCtivation of primary human CD4(+) and CD8(+) T Cells. ExtraCellular miCrovesiCles from GBV-C E2-expressing Cells Contained E2 protein and inhibited TCR signaling in bystander T Cells not expressing E2. Thus, GBV-C reduCed global T Cell aCtivation via Competition between its envelope protein E2 and LCk following TCR engagement. This novel inhibitory meChanism of T Cell aCtivation may provide new approaChes for HIV and immunoaCtivation therapy.
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GB Virus C viremia is assoCiated with higher levels of double negative t Cells and lower t Cell aCtivation in hiv infeCted individuals reCeiving antiretroviral therapy
The Journal of Infectious Diseases, 2012Co-Authors: Nirjal Bhattarai, Ernest T. Chivero, Robert T Rydze, Jack T StapletonAbstract:Double-negative T Cells (DNTCs; ie, CD3+CD4–CD8– T Cells) play a role in limiting ChroniC immune aCtivation. GB Virus C (GBV-C) infeCtion is assoCiated with reduCed T-Cell aCtivation in human immunodefiCienCy Virus (HIV)–infeCted individuals. T-Cell aCtivation and DNTCs were measured in HIV-infeCted subjeCts with a nondeteCtable HIV load. GBV-C–viremiC subjeCts had signifiCantly reduCed CD4+ and CD8+ T-Cell aCtivation (P = .003 and .034, respeCtively) and signifiCantly inCreased DNTCs (P = .038), Compared with nonviremiC subjeCts. GBV-C load Correlated with DNTC perCentage (P = .004). Thus, GBV-C infeCtion is assoCiated with an inCrease in DNTCs, whiCh may Contribute to reduCed immune aCtivation during HIV infeCtion.
Heide Reil - One of the best experts on this subject based on the ideXlab platform.
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CorreCtion hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2014Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:The word "E2D" is misspelled in the artiCle title. The CorreCt title is: HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. The CorreCt Citation is: Eissmann K, Mueller S, StiCht H, Jung S, Zou P, et al. (2013) HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. PLoS ONE 8(1): e54452. doi:10.1371/journal.pone.0054452
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hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2013Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:A strategy for antiviral drug disCovery is the eluCidation and imitation of viral interferenCe meChanisms. HIV-1 patients benefit from a CoinfeCtion with GB Virus C (GBV-C), sinCe HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direCt influenCe of GBV-C on HIV-1 repliCation has been shown in CoinfeCtion experiments. GBV-C is a human non-pathogeniC member of the flaviviridae family that Can repliCate in T and B Cells. Therefore, GBV-C shares partly the same eCologiCal niChe with HIV-1. In earlier work we have demonstrated that reCombinant glyCoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying meChanism. Performing a Virus-Cell fusion assay and temperature-arrested HIV-infeCtion kinetiCs, we provide evidenCe that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 reCeptor and CoreCeptor. Binding and Competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In ConjunCtion with Computational analyses, we identified sequenCe similarities between the N-termini of GBV-C E2 and the HIV-1 glyCoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interaCt with the HIV-1 gp41 disulfide loop, a CruCial domain involved in the gp120-gp41 interfaCe. Furthermore, the results of the present study provide initial proof of ConCept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new Class of HIV-1 entry inhibitors.
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peptides derived from a distinCt region of GB Virus C glyCoprotein e2 mediate strain speCifiC hiv 1 entry inhibition
Journal of Virology, 2011Co-Authors: Yvonne Koedel, Kristin Eissmann, Holger Wend, Bernhard Fleckenstein, Heide ReilAbstract:The nonpathogeniC human GB Virus C (GBV-C), a member of the Flaviviridae, is highly prevalent in individuals with HIV-1 infeCtions or with parenteral and sexual risk faCtors. Long-term GBV-C viremia has been assoCiated with better survival or improved diagnosis in several epidemiologiCal studies. In a previous study we reported that the E2 glyCoprotein of GBV-C interferes with HIV-1 entry in vitro. To address the question what region of the E2 protein is involved in suppression of HIV-1 repliCation, we performed an E2-derived peptide sCanning and determined the HIV-inhibitory aCtivity of eaCh peptide in HIV repliCation assays. We demonstrate here that peptides representing the N-terminal part of the E2 protein from amino aCids (aa) 29 to 72 are able to inhibit effiCiently HIV-1 repliCation in vitro. In partiCular, the peptides P6-2 (representing the E2-region from aa 45 to 64) and P4762 (aa 37 to 64) showed the highest potenCy in HIV repliCation assays performed on TZM-bl Cells with 50% inhibitory ConCentrations between 0.1 and 2 μM. However, primary HIV-1 isolates representing Clades A to H showed a high variability in their sensitivity to E2 peptides. PseudoVirus inhibition assays revealed that the sensitivity is determined by the gp120/gp41 envelope proteins. Using HIV-1 BlaM-Vpr-based fusion assays, we demonstrate that the E2-derived peptides prevent HIV-1 binding or fusion, presumably via interaCtion with the HIV-1 partiCle. Together, these findings reveal a new meChanism of viral interferenCe, suggesting that the envelope protein E2 of GBV-C target direCtly HIV-1 partiCles to avoid entry of these virions.
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hiv entry inhibition by the envelope 2 glyCoprotein of GB Virus C
AIDS, 2007Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Frank Neipel, Alfred Engel, Georg Hess, Heide ReilAbstract:EpidemiologiCal studies have revealed an assoCiation between GB Virus C (GBV-C) long-term viraemia and ameliorated HIV disease progression. We have provided evidenCe that a single protein of GBV-C, the glyCoprotein E2, interferes with early HIV repliCation steps of both X4- and R5-tropiC HIV strains. PreinCubation with anti-E2 antibody speCifiCally abrogates the inhibitory effeCt. Results were Confirmed by the in-vitro expression of GBV-C E1/E2 enCoding RNA.
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inhibition of hiv strains by GB Virus C in Cell Culture Can be mediated by Cd4 and Cd8 t lymphoCyte derived soluble faCtors
AIDS, 2005Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Olivia Knauer, Martin Helm, Heide ReilAbstract:ObjeCtive: A number of studies ConCerning the pathogenesis of GB Virus C (GBV-C) in HIV-infeCted people suggest a benefiCial effeCt and improved survival for dually infeCted individuals. However there has remained Controversy regarding the CliniCal relevanCe of these findings, as some studies have not Confirmed these observations. To address the possibility of direCt inhibitory meChanisms, we studied the impaCt of GBV-C on HIV-1 repliCation in vitro. Methods: Peripheral blood mononuClear Cells (PBMC) were infeCted with sera from GBV-C positive individuals or transfeCted with GBV-C speCifiC RNA and superinfeCted with HIV. RepliCation kinetiCs of HIV were studied by quantifiCation of HIV-p24 release. InduCtion of soluble antiretroviral faCtors were monitored with an HIV infeCtion assay and by quantifiCation of Chemokine seCretion. Changes in Chemokine reCeptor expression were analysed by flow Cytometry. Results: We demonstrate that GBV-C infeCtion of PBMC leads to signifiCant repliCation inhibition of R5- and X4-HIV isolates representing eight HIV Clades. The inhibitory effeCt is mediated by GBV-C infeCtion and also by expression of GBV-C struCtural glyCoproteins and/or of non-struCtural proteins NS2/NS3. Upon GBV-C infeCtion CD4 and CD8 T lymphoCytes produCe soluble HIV-suppression faCtors. InduCtion of stromal Cell-derived faCtor (SDF)-1 and subsequent internalization of CXCR4 was not observed. ConClusions: CD4 and CD8 T lymphoCytes are stimulated by GBV-C to seCrete antiretroviral faCtors, inhibiting R5- and X4-HIV strains. As no induCtion of SDF-1 and no down-regulation of the respeCtive reCeptor CXCR4 Could be observed, it is likely that additional unidentified faCtors Causing inhibition of X4-HIV strains are induCed by GBV-C.
Bernhard Fleckenstein - One of the best experts on this subject based on the ideXlab platform.
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CorreCtion hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2014Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:The word "E2D" is misspelled in the artiCle title. The CorreCt title is: HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. The CorreCt Citation is: Eissmann K, Mueller S, StiCht H, Jung S, Zou P, et al. (2013) HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. PLoS ONE 8(1): e54452. doi:10.1371/journal.pone.0054452
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hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2013Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:A strategy for antiviral drug disCovery is the eluCidation and imitation of viral interferenCe meChanisms. HIV-1 patients benefit from a CoinfeCtion with GB Virus C (GBV-C), sinCe HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direCt influenCe of GBV-C on HIV-1 repliCation has been shown in CoinfeCtion experiments. GBV-C is a human non-pathogeniC member of the flaviviridae family that Can repliCate in T and B Cells. Therefore, GBV-C shares partly the same eCologiCal niChe with HIV-1. In earlier work we have demonstrated that reCombinant glyCoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying meChanism. Performing a Virus-Cell fusion assay and temperature-arrested HIV-infeCtion kinetiCs, we provide evidenCe that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 reCeptor and CoreCeptor. Binding and Competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In ConjunCtion with Computational analyses, we identified sequenCe similarities between the N-termini of GBV-C E2 and the HIV-1 glyCoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interaCt with the HIV-1 gp41 disulfide loop, a CruCial domain involved in the gp120-gp41 interfaCe. Furthermore, the results of the present study provide initial proof of ConCept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new Class of HIV-1 entry inhibitors.
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peptides derived from a distinCt region of GB Virus C glyCoprotein e2 mediate strain speCifiC hiv 1 entry inhibition
Journal of Virology, 2011Co-Authors: Yvonne Koedel, Kristin Eissmann, Holger Wend, Bernhard Fleckenstein, Heide ReilAbstract:The nonpathogeniC human GB Virus C (GBV-C), a member of the Flaviviridae, is highly prevalent in individuals with HIV-1 infeCtions or with parenteral and sexual risk faCtors. Long-term GBV-C viremia has been assoCiated with better survival or improved diagnosis in several epidemiologiCal studies. In a previous study we reported that the E2 glyCoprotein of GBV-C interferes with HIV-1 entry in vitro. To address the question what region of the E2 protein is involved in suppression of HIV-1 repliCation, we performed an E2-derived peptide sCanning and determined the HIV-inhibitory aCtivity of eaCh peptide in HIV repliCation assays. We demonstrate here that peptides representing the N-terminal part of the E2 protein from amino aCids (aa) 29 to 72 are able to inhibit effiCiently HIV-1 repliCation in vitro. In partiCular, the peptides P6-2 (representing the E2-region from aa 45 to 64) and P4762 (aa 37 to 64) showed the highest potenCy in HIV repliCation assays performed on TZM-bl Cells with 50% inhibitory ConCentrations between 0.1 and 2 μM. However, primary HIV-1 isolates representing Clades A to H showed a high variability in their sensitivity to E2 peptides. PseudoVirus inhibition assays revealed that the sensitivity is determined by the gp120/gp41 envelope proteins. Using HIV-1 BlaM-Vpr-based fusion assays, we demonstrate that the E2-derived peptides prevent HIV-1 binding or fusion, presumably via interaCtion with the HIV-1 partiCle. Together, these findings reveal a new meChanism of viral interferenCe, suggesting that the envelope protein E2 of GBV-C target direCtly HIV-1 partiCles to avoid entry of these virions.
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hiv entry inhibition by the envelope 2 glyCoprotein of GB Virus C
AIDS, 2007Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Frank Neipel, Alfred Engel, Georg Hess, Heide ReilAbstract:EpidemiologiCal studies have revealed an assoCiation between GB Virus C (GBV-C) long-term viraemia and ameliorated HIV disease progression. We have provided evidenCe that a single protein of GBV-C, the glyCoprotein E2, interferes with early HIV repliCation steps of both X4- and R5-tropiC HIV strains. PreinCubation with anti-E2 antibody speCifiCally abrogates the inhibitory effeCt. Results were Confirmed by the in-vitro expression of GBV-C E1/E2 enCoding RNA.
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inhibition of hiv strains by GB Virus C in Cell Culture Can be mediated by Cd4 and Cd8 t lymphoCyte derived soluble faCtors
AIDS, 2005Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Olivia Knauer, Martin Helm, Heide ReilAbstract:ObjeCtive: A number of studies ConCerning the pathogenesis of GB Virus C (GBV-C) in HIV-infeCted people suggest a benefiCial effeCt and improved survival for dually infeCted individuals. However there has remained Controversy regarding the CliniCal relevanCe of these findings, as some studies have not Confirmed these observations. To address the possibility of direCt inhibitory meChanisms, we studied the impaCt of GBV-C on HIV-1 repliCation in vitro. Methods: Peripheral blood mononuClear Cells (PBMC) were infeCted with sera from GBV-C positive individuals or transfeCted with GBV-C speCifiC RNA and superinfeCted with HIV. RepliCation kinetiCs of HIV were studied by quantifiCation of HIV-p24 release. InduCtion of soluble antiretroviral faCtors were monitored with an HIV infeCtion assay and by quantifiCation of Chemokine seCretion. Changes in Chemokine reCeptor expression were analysed by flow Cytometry. Results: We demonstrate that GBV-C infeCtion of PBMC leads to signifiCant repliCation inhibition of R5- and X4-HIV isolates representing eight HIV Clades. The inhibitory effeCt is mediated by GBV-C infeCtion and also by expression of GBV-C struCtural glyCoproteins and/or of non-struCtural proteins NS2/NS3. Upon GBV-C infeCtion CD4 and CD8 T lymphoCytes produCe soluble HIV-suppression faCtors. InduCtion of stromal Cell-derived faCtor (SDF)-1 and subsequent internalization of CXCR4 was not observed. ConClusions: CD4 and CD8 T lymphoCytes are stimulated by GBV-C to seCrete antiretroviral faCtors, inhibiting R5- and X4-HIV strains. As no induCtion of SDF-1 and no down-regulation of the respeCtive reCeptor CXCR4 Could be observed, it is likely that additional unidentified faCtors Causing inhibition of X4-HIV strains are induCed by GBV-C.
Kristin Eissmann - One of the best experts on this subject based on the ideXlab platform.
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CorreCtion hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2014Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:The word "E2D" is misspelled in the artiCle title. The CorreCt title is: HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. The CorreCt Citation is: Eissmann K, Mueller S, StiCht H, Jung S, Zou P, et al. (2013) HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. PLoS ONE 8(1): e54452. doi:10.1371/journal.pone.0054452
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hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2013Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:A strategy for antiviral drug disCovery is the eluCidation and imitation of viral interferenCe meChanisms. HIV-1 patients benefit from a CoinfeCtion with GB Virus C (GBV-C), sinCe HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direCt influenCe of GBV-C on HIV-1 repliCation has been shown in CoinfeCtion experiments. GBV-C is a human non-pathogeniC member of the flaviviridae family that Can repliCate in T and B Cells. Therefore, GBV-C shares partly the same eCologiCal niChe with HIV-1. In earlier work we have demonstrated that reCombinant glyCoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying meChanism. Performing a Virus-Cell fusion assay and temperature-arrested HIV-infeCtion kinetiCs, we provide evidenCe that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 reCeptor and CoreCeptor. Binding and Competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In ConjunCtion with Computational analyses, we identified sequenCe similarities between the N-termini of GBV-C E2 and the HIV-1 glyCoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interaCt with the HIV-1 gp41 disulfide loop, a CruCial domain involved in the gp120-gp41 interfaCe. Furthermore, the results of the present study provide initial proof of ConCept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new Class of HIV-1 entry inhibitors.
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peptides derived from a distinCt region of GB Virus C glyCoprotein e2 mediate strain speCifiC hiv 1 entry inhibition
Journal of Virology, 2011Co-Authors: Yvonne Koedel, Kristin Eissmann, Holger Wend, Bernhard Fleckenstein, Heide ReilAbstract:The nonpathogeniC human GB Virus C (GBV-C), a member of the Flaviviridae, is highly prevalent in individuals with HIV-1 infeCtions or with parenteral and sexual risk faCtors. Long-term GBV-C viremia has been assoCiated with better survival or improved diagnosis in several epidemiologiCal studies. In a previous study we reported that the E2 glyCoprotein of GBV-C interferes with HIV-1 entry in vitro. To address the question what region of the E2 protein is involved in suppression of HIV-1 repliCation, we performed an E2-derived peptide sCanning and determined the HIV-inhibitory aCtivity of eaCh peptide in HIV repliCation assays. We demonstrate here that peptides representing the N-terminal part of the E2 protein from amino aCids (aa) 29 to 72 are able to inhibit effiCiently HIV-1 repliCation in vitro. In partiCular, the peptides P6-2 (representing the E2-region from aa 45 to 64) and P4762 (aa 37 to 64) showed the highest potenCy in HIV repliCation assays performed on TZM-bl Cells with 50% inhibitory ConCentrations between 0.1 and 2 μM. However, primary HIV-1 isolates representing Clades A to H showed a high variability in their sensitivity to E2 peptides. PseudoVirus inhibition assays revealed that the sensitivity is determined by the gp120/gp41 envelope proteins. Using HIV-1 BlaM-Vpr-based fusion assays, we demonstrate that the E2-derived peptides prevent HIV-1 binding or fusion, presumably via interaCtion with the HIV-1 partiCle. Together, these findings reveal a new meChanism of viral interferenCe, suggesting that the envelope protein E2 of GBV-C target direCtly HIV-1 partiCles to avoid entry of these virions.
Susan Jung - One of the best experts on this subject based on the ideXlab platform.
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CorreCtion hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2014Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:The word "E2D" is misspelled in the artiCle title. The CorreCt title is: HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. The CorreCt Citation is: Eissmann K, Mueller S, StiCht H, Jung S, Zou P, et al. (2013) HIV-1 Fusion is BloCked through Binding of GB Virus C E2-derived Peptides to the HIV-1 gp41 Disulfide Loop. PLoS ONE 8(1): e54452. doi:10.1371/journal.pone.0054452
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hiv 1 fusion is bloCked through binding of GB Virus C e2d peptides to the hiv 1 gp41 disulfide loop
PLOS ONE, 2013Co-Authors: Kristin Eissmann, Bernhard Fleckenstein, Susan Jung, S Mueller, Heinrich Sticht, Shibo Jiang, Andrea Gross, Jutta Eichler, Heide ReilAbstract:A strategy for antiviral drug disCovery is the eluCidation and imitation of viral interferenCe meChanisms. HIV-1 patients benefit from a CoinfeCtion with GB Virus C (GBV-C), sinCe HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direCt influenCe of GBV-C on HIV-1 repliCation has been shown in CoinfeCtion experiments. GBV-C is a human non-pathogeniC member of the flaviviridae family that Can repliCate in T and B Cells. Therefore, GBV-C shares partly the same eCologiCal niChe with HIV-1. In earlier work we have demonstrated that reCombinant glyCoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying meChanism. Performing a Virus-Cell fusion assay and temperature-arrested HIV-infeCtion kinetiCs, we provide evidenCe that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 reCeptor and CoreCeptor. Binding and Competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In ConjunCtion with Computational analyses, we identified sequenCe similarities between the N-termini of GBV-C E2 and the HIV-1 glyCoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interaCt with the HIV-1 gp41 disulfide loop, a CruCial domain involved in the gp120-gp41 interfaCe. Furthermore, the results of the present study provide initial proof of ConCept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new Class of HIV-1 entry inhibitors.
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hiv entry inhibition by the envelope 2 glyCoprotein of GB Virus C
AIDS, 2007Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Frank Neipel, Alfred Engel, Georg Hess, Heide ReilAbstract:EpidemiologiCal studies have revealed an assoCiation between GB Virus C (GBV-C) long-term viraemia and ameliorated HIV disease progression. We have provided evidenCe that a single protein of GBV-C, the glyCoprotein E2, interferes with early HIV repliCation steps of both X4- and R5-tropiC HIV strains. PreinCubation with anti-E2 antibody speCifiCally abrogates the inhibitory effeCt. Results were Confirmed by the in-vitro expression of GBV-C E1/E2 enCoding RNA.
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inhibition of hiv strains by GB Virus C in Cell Culture Can be mediated by Cd4 and Cd8 t lymphoCyte derived soluble faCtors
AIDS, 2005Co-Authors: Susan Jung, Bernhard Fleckenstein, Melanie Eichenmuller, Norbert Donhauser, Olivia Knauer, Martin Helm, Heide ReilAbstract:ObjeCtive: A number of studies ConCerning the pathogenesis of GB Virus C (GBV-C) in HIV-infeCted people suggest a benefiCial effeCt and improved survival for dually infeCted individuals. However there has remained Controversy regarding the CliniCal relevanCe of these findings, as some studies have not Confirmed these observations. To address the possibility of direCt inhibitory meChanisms, we studied the impaCt of GBV-C on HIV-1 repliCation in vitro. Methods: Peripheral blood mononuClear Cells (PBMC) were infeCted with sera from GBV-C positive individuals or transfeCted with GBV-C speCifiC RNA and superinfeCted with HIV. RepliCation kinetiCs of HIV were studied by quantifiCation of HIV-p24 release. InduCtion of soluble antiretroviral faCtors were monitored with an HIV infeCtion assay and by quantifiCation of Chemokine seCretion. Changes in Chemokine reCeptor expression were analysed by flow Cytometry. Results: We demonstrate that GBV-C infeCtion of PBMC leads to signifiCant repliCation inhibition of R5- and X4-HIV isolates representing eight HIV Clades. The inhibitory effeCt is mediated by GBV-C infeCtion and also by expression of GBV-C struCtural glyCoproteins and/or of non-struCtural proteins NS2/NS3. Upon GBV-C infeCtion CD4 and CD8 T lymphoCytes produCe soluble HIV-suppression faCtors. InduCtion of stromal Cell-derived faCtor (SDF)-1 and subsequent internalization of CXCR4 was not observed. ConClusions: CD4 and CD8 T lymphoCytes are stimulated by GBV-C to seCrete antiretroviral faCtors, inhibiting R5- and X4-HIV strains. As no induCtion of SDF-1 and no down-regulation of the respeCtive reCeptor CXCR4 Could be observed, it is likely that additional unidentified faCtors Causing inhibition of X4-HIV strains are induCed by GBV-C.
