Selective Regulation of Human Immunodeficiency Virus-Infected CD4<sup>+</sup>Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice

Bahr, George M.; Darcissac, Edith; Castéran, Nathalie; Amiel, Corinne; Cocude, Cécile; Truong, Marie‐José; Dewulf, Joëlle; Càpron, André; Mouton, Y

doi:10.1128/jvi.75.15.6941-6952.2001

Cited by 18 publications

(10 citation statements)

References 72 publications

(70 reference statements)

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“…Interestingly, the role of Oct-1 in HIV-1 transcription has also been indirectly highlighted by Bahr and co-workers. They have demonstrated that murabutide, which is a clinically acceptable immunomodulator presenting the capacity to decrease HIV-1 transcription (43,44), presents the ability to induce Oct-1 expression and DNA-binding activity in HIV-1 infected macrophages (45). These results suggest that the murabutide-induced suppression of HIV-1 transcription could be mediated, at least in part, by its capacity to increase Oct-1 expression (45).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Goffin¹

2005

Nucleic Acids Research

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We have previously identified in the pol gene of human immunodeficiency virus type 1 (HIV-1) a new positive transcriptional regulatory element (nt 4481–4982) containing recognition sites for nuclear proteins (sites B, C, D and a GC-box) [C. Van Lint, J. Ghysdael, P. Paras, Jr, A. Burny and E. Verdin (1994) J. Virol. 68, 2632–2648]. In this study, we have further physically characterized each binding site and have shown that the transcription factors Oct-1, Oct-2, PU.1, Sp1 and Sp3 interact in vitro with the pol region. Chromatin immunoprecipitation assays using HIV-infected cell lines demonstrated in the context of chromatin that Sp1, Sp3, Oct-1 and PU.1 are recruited to the HS7 region in vivo. For each site, we have identified mutations abolishing factor binding to their cognate DNA sequences without altering the underlying amino acid sequence of the integrase. By transient transfection assays, we have demonstrated the involvement of the pol binding sites in the transcriptional enhancing activity of the intragenic region. Our functional results with multimerized wild-type and mutated pol binding sites separately (i.e. in the absence of the other sites) have demonstrated that the PU.1, Sp1, Sp3 and Oct-1 transcription factors regulate the transcriptional activity of a heterologous promoter through their respective HS7 binding sites. Finally, we have investigated the physiological role of the HS7 binding sites in HIV-1 replication and have shown that these sites are important for viral infectivity.

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Section: Discussionmentioning

confidence: 99%

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Goffin¹

2005

Nucleic Acids Research

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“…Romurtide and B30‐MDP 8 were found to limit infection by herpes simplex virus type 1, herpes simplex virus type 2 and vaccinia virus . Moreover, murabutide 10 has been shown to limit HIV‐1 viral loads in a humanised murine model . However, it remains uncertain whether these effects are truly via long‐term epigenetic reprogramming as many of the assays were conducted soon after adjuvant administration.…”

Section: Peptidoglycan Metabolites and Adjuvanticitymentioning

confidence: 99%

“…105 Moreover, murabutide 10 has been shown to limit HIV-1 viral loads in a humanised murine model. 106 However, it remains uncertain whether these effects are truly via long-term epigenetic reprogramming as many of the assays were conducted soon after adjuvant administration.…”

Section: Peptidoglycan Metabolites and Adjuvanticitymentioning

confidence: 99%

Translation of peptidoglycan metabolites into immunotherapeutics

et al. 2019

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The discovery of defined peptidoglycan metabolites that activate host immunity and their specific receptors has revealed fundamental insights into host–microbe recognition and afforded new opportunities for therapeutic development against infection and cancer. In this review, we summarise the discovery of two key peptidoglycan metabolites, γ‐d‐glutamyl‐meso‐diaminopimelic acid (iE‐DAP) and muramyl dipeptide and their respective receptors, Nod1 and Nod2, and review progress towards translating these findings into therapeutic agents. Notably, synthetic derivatives of peptidoglycan metabolites have already yielded approved drugs for chemotherapy‐induced leukopenia and paediatric osteosarcoma; however, the broad effects of peptidoglycan metabolites on host immunity suggest additional translational opportunities for new therapeutics towards other cancers, microbial infections and inflammatory diseases.

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“…Additional support for the capacity of MB to regulate the expression of cellular genes, and consequently to inhibit viral replication, has been provided by a recent study using endogeneously infected lymphocytes. Thus, MB‐treated CD4 + cells from HIV‐infected patients were found to down‐regulate the expression of c‐myc, a host factor known to be essential for the nuclear transport of preintegration complexes in activated T‐lymphocytes [20].…”

Section: Introductionmentioning

confidence: 96%

The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator

Goasduff

Darcissac

Vidal

et al. 2002

Clinical and Experimental Immunology

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SUMMARY The synthetic immunomodulator murabutide (MB) presents multiple biological activities with minimal toxicity in animals and in man. Although MB is known to target cells of the reticuloendothelial system and to regulate cytokine synthesis, the molecular mechanisms underlying several of its biological effects are still largely unknown. In an effort to define cellular factors implicated in the immunomodulatory and HIV‐suppressive activities of MB, we have undertaken profiling the regulated expression of genes in human monocyte‐derived macrophages (MDM) following a 6‐h stimulation with this synthetic glycopeptide. Oligonucleotide microarray analysis was performed on RNA samples of differentiated MDM from four separate donors, using probe sets corresponding to 1081 genes. We have identified, in a reproducible fashion, the enhanced expression of 40 genes and the inhibition of 16 others in MB‐treated MDM. These regulated genes belonged to different families of immune mediators or their receptors, transcription factors and kinases, matrix proteins and their inhibitors, ion channels and transporters, and proteins involved in cell metabolic pathways. Additional verification of the regulated expression of selected genes was carried out using Northern blots or the quantification of released proteins in MDM cultures. The profile of MB‐regulated genes in MDM provides a molecular basis for some of its previously reported biological activities, and reveals new set of genes targeted by the immunomodulator suggesting potential application in novel therapeutic indications.

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Selective Regulation of Human Immunodeficiency Virus-Infected CD4⁺Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice

Abstract: We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells.

Cited by 18 publications

References 72 publications

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Translation of peptidoglycan metabolites into immunotherapeutics

The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator

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Selective Regulation of Human Immunodeficiency Virus-Infected CD4+Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice

Abstract: We have previously observed that the synthetic immunomodulator Murabutide inhibits human immunodeficiency virus type 1 (HIV-1) replication at multiple levels in macrophages and dendritic cells.

Cited by 18 publications

References 72 publications

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity

Translation of peptidoglycan metabolites into immunotherapeutics

The transcriptional response of human macrophages to murabutide reflects a spectrum of biological effects for the synthetic immunomodulator

Contact Info

Product

Resources

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Selective Regulation of Human Immunodeficiency Virus-Infected CD4⁺Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice