Reactivation of latent HIV-1 in vitro using an ethanolic extract from Euphorbia umbellata (Euphorbiaceae) latex

Euphorbia umbellata (E. umbellata) belongs to Euphorbiaceae family, popularly known as Janauba, and its latex contains a combination of phorbol esters with biological activities described to different cellular protein kinase C (PKC) isoforms. Here, we identified deoxi-phorbol esters present in E. umbellata latex alcoholic extract that are able to increase HIV transcription and reactivate virus from latency models. This activity is probably mediated by NF-kB activation followed by nuclear translocation and binding to the HIV LTR promoter. In addition, E. umbellata latex extract induced the production of pro inflammatory cytokines in vitro in human PBMC cultures. This latex extract also activates latent virus in human PBMCs isolated from HIV positive patients as well as latent SIV in non-human primate primary CD4+ T lymphocytes. Together, these results indicate that the phorbol esters present in E. umbellata latex are promising candidate compounds for future clinical trials for shock and kill therapies to promote HIV cure and eradication.Research and experimental expenses were funded by the grant E26/2015064289 from FAPERJinfo:eu-repo/semantics/publishedVersio

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil

Submitted by Fábio Marques ([email protected]) on 2019-06-10T19:10:10Z No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-06-10T19:34:37Z (GMT) No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5)Made available in DSpace on 2019-06-10T19:34:37Z (GMT). No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5) Previous issue date: 2019Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST-AIDS. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro, Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.BACKGROUND: Dengue is an arthropod-borne viral disease with a majority of asymptomatic individuals and clinical manifestations varying from mild fever to severe and potentially lethal forms. An increasing number of genetic studies have outlinedthe association between host genetic variations and dengue severity. Genes associated to viral recognition and entry, as well as those encoding mediators of the immune response against infection are strong candidates for association studies. OBJECTIVES: The aim of this study was to investigate the association between MBL2, CLEC5A, ITGB3 and CCR5 genes and dengue severity in children. METHODS: A matched case-control study was conducted and 19 single nucleotide polymorphisms (SNPs) were investigated. FINDINGS: No associations were observed in single SNP analysis. However, when MBL2 SNPs were combined in haplotypes, the allele rs7095891G/rs1800450C/ rs1800451C/rs4935047A/rs930509G/rs2120131G/rs2099902C was significantly associated to risk of severe dengue under α = 0.05 (aOR = 4.02; p = 0.02). A second haplotype carrying rs4935047G and rs7095891G alleles was also associated to risk (aOR = 1.91; p = 0.04). MAIN CONCLUSIONS: This is the first study to demonstrate the association between MBL2 haplotypes and dengue severity in Brazilians including adjustment for genetic ancestry. These results reinforce the role of mannose binding lectin in immune response to DENV

Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39+Treg cell subsets in response to myelin antigen in multiple sclerosis patients.

BackgroundMood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells.ObjectivesWe aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients.MethodsFor our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated.ResultsHere, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen.ConclusionsIn summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity

Association between Maternal Non-Coding Interferon-λ Polymorphisms and Congenital Zika Syndrome in a Cohort from Brazilian Northeast

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case–control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (adjustedOR = 2.80; 95%CI = 1.14–6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts

Association between Maternal Non-Coding Interferon-λ Polymorphisms and Congenital Zika Syndrome in a Cohort from Brazilian Northeast

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case–control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (adjustedOR = 2.80; 95%CI = 1.14–6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts

Congenital Zika syndrome is associated with maternal protein malnutrition

MRC Zika Rapid Response Grant (MC_PC_15102), FAPERJ (E_03/2017E_03/2017), the Brazilian Ministry of Health (DSAST/SVS 25380.001612/2017-70), and the AAPA Professional Development GrantFederal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil / Institute for Studies in Neuroscience and Complex Systems. Buenos Aires, Argentina.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Microbiology Institute Paulo de Góes. Rio de Janeiro, RJ, Brazil.Federal University of Pará. Biological Science Institute. Belém, PA, Brazil.Federal University of Rio de Janeiro. Nuclear Instrumentation Laboratory. Rio de Janeiro RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Microbiology Institute Paulo de Góes. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.National Center of Structural Biology and Bioimaging. Rio de Janeiro, RJ, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Centro de Inovações tecnológicas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Centro de Inovações tecnológicas. Ananindeua, PA, Brasil.State Institute of Brain Paulo Niemeyer. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Institute for Studies in Neuroscience and Complex Systems. Buenos Aires, Argentina.Fundação Oswaldo Cruz. Oswaldo Cruz Institute. Rio de Janeiro, RJ, Brazil.Harvard T. H. Chan School of Public Health. Department of Global Health and Population. Boston, MA, USA.Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS