Human Immunodeficiency Virus (#HIV)–Infected CCR6+ #Rectal CD4+ T Cells and HIV #Persistence On #Antiretroviral Therapy (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Human Immunodeficiency Virus (HIV)–Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy

Jenny L Anderson, Gabriela Khoury, Rémi Fromentin, Ajantha Solomon, Nicolas Chomont, Elizabeth Sinclair, Jeffrey M Milush, Wendy Hartogensis, Peter Bacchetti, Michael Roche, Carolin Tumpach, Matthew Gartner, Matthew C Pitman, Christine Lorrie Epling, Rebecca Hoh, Frederick M Hecht, Ma Somsouk, Paul U Cameron, Steven G Deeks, Sharon R Lewin

The Journal of Infectious Diseases, jiz509, https://doi.org/10.1093/infdis/jiz509

Published: 04 December 2019

 

Abstract

Background

Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.

Methods

Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.

Results

Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.

Conclusions

HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.

HIV reservoir, latency, persistence, chemokine receptor, CCR6, CXCR3, chemokines, rectal tissue, lymph node

Issue Section: Major Article

Keywords: HIV/AIDS; Antivirals; Immunopathology.

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Long-Term #Complications of #Ebola Virus Disease: #Prevalence and #Predictors of Major #Symptoms and the Role of #Inflammation (Clin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2019 Nov 6. pii: ciz1062. doi: 10.1093/cid/ciz1062. [Epub ahead of print]

Long-Term Complications of Ebola Virus Disease: Prevalence and Predictors of Major Symptoms and the Role of Inflammation.

Tozay S1, Fischer WA2,3, Wohl DA3,4, Kilpatrick K5, Zou F5, Reeves E1, Pewu K1, DeMarco J3, Loftis AJ3,4, King K3, Grant D3, Schieffelin J3, Gorvego G1, Johnson H1, Conneh T1, Williams G1, Nelson JAE6, Hoover D7, McMillian D3, Merenbloom C3, Hawks D3, Dube K3, Brown J1.

Author information: 1 Eternal Love Winning Africa Hospital, Paynesville, Liberia. 2 Division of Pulmonary and Critical Care Medicine, The University of North Carolina, Chapel Hill, North Carolina, United States of America. 3 The Institute of Global Health and Infectious Diseases, The University of North Carolina, Chapel Hill, North Carolina, United States of America. 4 Division of Infectious Diseases, The University of North Carolina, Chapel Hill, North Carolina, United States of America. 5 Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina, United States of America. 6 Department of Microbiology and Immunology, The University of North Carolina, Chapel Hill, North Carolina, United States of America. 7 ICON Government and Public Health Solutions (formerly Clinical RM), Leopardstown, Dublin, Ireland.

 

Abstract

BACKGROUND:

Cohort studies have reported a high prevalence of musculoskeletal, neurologic, auditory, and visual complications among Ebola Virus Disease (EVD) survivors; however, little is known about the host- and disease-related predictors of these symptoms and their etiological mechanisms.

METHODS:

The presence and patterns of eight cardinal symptoms that are most commonly reported following EVD survival were assessed in the 326 EVD survivors participating in the ongoing longitudinal Liberian EVD Survivor Study. At quarterly study visits, symptoms that developed since acute EVD were recorded and blood was collected for biomarkers of inflammation and immune activation.

RESULTS:

At baseline (mean 408 days from acute EVD), 75.5% of survivors reported at least one new cardinal symptom since surviving EVD, which in 85.8% was rated as highly interfering with life. Two or more incident symptoms were reported by 61.0% of survivors with pairings of joint pain, headache, or fatigue the most frequent. Women were significantly more likely than men to report headache while older age was significantly associated with musculoskeletal and visual symptoms. In analyses adjusted for multiple comparisons, no statistically significant association was found between any symptom and 26 markers of inflammation and immune activation. Symptom frequency remained largely unchanged during study follow-up.

CONCLUSIONS:

Post-EVD complications occur in a majority of survivors and remain present more than 4 years after acute infection. An association between markers of inflammation and immune activation and individual symptoms was not found, suggesting an alternative etiology for persistent post-EVD symptomatology.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Ebola virus disease; Inflammation; Post-EVD Complications; Survivors

PMID: 31693114 DOI: 10.1093/cid/ciz1062

Keywords: Ebola; Immunopathology.

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#Measles virus #infection diminishes preexisting #antibodies that offer #protection from other #pathogens (Science, abstract)

[Source: Science, full page: (LINK). Abstract, edited.]

Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens

Michael J. Mina1,2,3,*,†, Tomasz Kula1,2, Yumei Leng1, Mamie Li2, Rory D. de Vries4, Mikael Knip5,6, Heli Siljander5,6, Marian Rewers7, David F. Choy8, Mark S. Wilson8, H. Benjamin Larman9, Ashley N. Nelson10,‡, Diane E. Griffin10, Rik L. de Swart4, Stephen J. Elledge1,2,11,†

1 Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. 2 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. 3 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 4 Department of Viroscience, Postgraduate School of Molecular Medicine, Erasmus MC, University Medical Centre Rotterdam, 3015 CN, Rotterdam, Netherlands. 5 Children’s Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland. 6 Research Program for Clinical and Molecular Metabolism, University of Helsinki, 00014 Helsinki, Finland. 7 Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Denver, CO 80045, USA. 8 Genentech Inc., South San Francisco, CA 94080, USA. 9 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 10 W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. 11 Program in Virology, Harvard Medical School, Boston, MA 02115, USA.

†Corresponding author. Email: selledge@genetics.med.harvard.edu (S.J.E.); mmina@hsph.harvard.edu (M.J.M.)

* Present address: Center for Communicable Disease Dynamics, Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

‡ Present address: Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.

Science  01 Nov 2019: Vol. 366, Issue 6465, pp. 599-606 / DOI: 10.1126/science.aay6485

 

The toll of measles on the immune system

Many of the deaths attributable to measles virus are caused by secondary infections because the virus infects and functionally impairs immune cells. Whether measles infection causes long-term damage to immune memory has been unclear. This question has become increasingly important given the resurgence in measles epidemics worldwide. Using a blood test called VirScan, Mina et al. comprehensively analyzed the antibody repertoire in children before and after natural infection with measles virus as well as in children before and after measles vaccination. They found that measles infection can greatly diminish previously acquired immune memory, potentially leaving individuals at risk for infection by other pathogens. These adverse effects on the immune system were not seen in vaccinated children.

Science, this issue p. 599

 

Abstract

Measles virus is directly responsible for more than 100,000 deaths yearly. Epidemiological studies have associated measles with increased morbidity and mortality for years after infection, but the reasons why are poorly understood. Measles virus infects immune cells, causing acute immune suppression. To identify and quantify long-term effects of measles on the immune system, we used VirScan, an assay that tracks antibodies to thousands of pathogen epitopes in blood. We studied 77 unvaccinated children before and 2 months after natural measles virus infection. Measles caused elimination of 11 to 73% of the antibody repertoire across individuals. Recovery of antibodies was detected after natural reexposure to pathogens. Notably, these immune system effects were not observed in infants vaccinated against MMR (measles, mumps, and rubella), but were confirmed in measles-infected macaques. The reduction in humoral immune memory after measles infection generates potential vulnerability to future infections, underscoring the need for widespread vaccination.

Keywords: Measles; Immunopathology.

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#Cytokine Induction in #Nipah Virus–Infected Primary #Human and #Porcine #Bronchial Epithelial Cells (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Cytokine Induction in Nipah Virus–Infected Primary Human and Porcine Bronchial Epithelial Cells

Mareike Elvert, Lucie Sauerhering, Andrea Maisner

The Journal of Infectious Diseases, jiz455, https://doi.org/10.1093/infdis/jiz455

Published: 30 October 2019

 

Abstract

During the Nipah virus (NiV) outbreak in Malaysia, pigs and humans were infected. While pigs generally developed severe respiratory disease due to an effective virus replication and associated inflammation processes in the porcine airways, respiratory symptoms in humans were rare and less severe. To elucidate the reasons for the species-specific differences in NiV airway infections, we compared the cytokine responses as a first reaction to NiV in primary porcine and human bronchial epithelial cells (PBEpC and HBEpC, respectively). In both cell types, NiV infections resulted in the expression of type III interferons (IFN-λ). Upon infections with similar virus doses, the viral RNA load and IFN expression were substantially higher in HBEpC. Even if PBEpC expressed the same viral RNA amounts as NiV-infected HBEpC, the porcine cells showed a reduced IFN- and IFN-dependent antiviral gene expression. Despite this inherently limited IFN response, the expression of proinflammatory cytokines (IL-6, IL-8) in NiV-infected PBEpC was not decreased. The downregulation of the antiviral activity in the presence of a functional proinflammatory cytokine response might be one of the species-specific factors contributing to efficient virus replication and acute inflammation in the lungs of pigs infected with the Malaysian NiV strain.

Nipah virus, primary bronchial epithelia, IFN-λ

Topic: cytokine – inflammation – lung – antiviral agents – disease outbreaks –  interferons – interleukin-8 – malaysia – rna, viral – signs and symptoms, respiratory – suidae – virus replication – infection – interleukin-6 – viruses – epithelial cells – airway device – nipah virus – nipah virus infections

Issue Section: Supplement Article

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Nipah virus; Cytokines; Immunopathology; Viral pathogenesis.

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#Ebola virus-mediated T- #lymphocyte #depletion is the result of an abortive #infection (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection

Patrick Younan , Rodrigo I. Santos , Palaniappan Ramanathan , Mathieu Iampietro, Andrew Nishida, Mukta Dutta, Tatiana Ammosova, Michelle Meyer, Michael G. Katze, Vsevolod L. Popov, Sergei Nekhai, Alexander Bukreyev

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Published: October 24, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008068

 

Abstract

Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.

 

Author summary

Lymphopenia is a common characteristic of the disease caused by EBOV. We determined that despite the apparent lack of productive infection, EBOV is capable of entering T cells and producing both viral RNAs and proteins. Furthermore, we demonstrate that EBOV causes an abortive infection in T cells due to the presence of a cellular restriction factor. The abortive infection was associated with cell death following ER-stress induced autophagy. Collectively, these findings suggest that abortive infection in T cells is likely to contribute to lymphopenia during Ebola virus disease, which is uniformly linked with the severity of the disease. All EBOV vaccine candidates utilize GP as the sole antigen inducing a protective antibody response and in some clinical trials were shown to induce adverse side effects. The present study suggests that these effects can be associated with GP, which may lead to abortive infection of the vaccine construct in T cells contributing to the inflammatory response to the vaccines.

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Citation: Younan P, Santos RI, Ramanathan P, Iampietro M, Nishida A, Dutta M, et al. (2019) Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection. PLoS Pathog 15(10): e1008068. https://doi.org/10.1371/journal.ppat.1008068

Editor: Yoshihiro Kawaoka, University of Wisconsin-Madison, UNITED STATES

Received: March 6, 2019; Accepted: September 3, 2019; Published: October 24, 2019

Copyright: © 2019 Younan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was supported by the NIH grant U19 AI109945-01 Project 2 Molecular Basis for Ebola Virus Immune Paralysis (A.B.) and NIH grant 1R01AI102887-01A1 (A.B.). Sound Genomics, a service center of the Washington National Primate Research Center performed the mRNA sequencing and is supported by funds from the National Institutes of Health, the Office of the Director (Grant P51OD010425). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Ebola; Immunopathology; Viral pathogenesis.

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Recent #advances in the understanding of #Nipah virus #immunopathogenesis and #antiviral approaches (F1000Res., abstract)

[Source: F1000 Research, full page: (LINK). Abstract, edited.]

Recent advances in the understanding of Nipah virus immunopathogenesis and anti-viral approaches

[version 1; peer review: 3 approved]

Rodolphe Pelissier*, Mathieu Iampietro*, Branka Horvat

* Equal contributors

Author details: International Center for Infectiology Research-CIRI, Immunobiology of Viral Infections team, Inserm U1111, CNRS, UMR5308, University of Lyon, Ecole Normale Supérieure de Lyon, France

 

Abstract

Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that emerged at the end of last century as a human pathogen capable of causing severe acute respiratory infection and encephalitis. Although NiV provokes serious diseases in numerous mammalian species, the infection seems to be asymptomatic in NiV natural hosts, the fruit bats, which provide a continuous virus source for further outbreaks. Consecutive human-to-human transmission has been frequently observed during outbreaks in Bangladesh and India. NiV was shown to interfere with the innate immune response and interferon type I signaling, restraining the anti-viral response and permitting viral spread. Studies of adaptive immunity in infected patients and animal models have suggested an unbalanced immune response during NiV infection. Here, we summarize some of the recent studies of NiV pathogenesis and NiV-induced modulation of both innate and adaptive immune responses, as well as the development of novel prophylactic and therapeutic approaches, necessary to control this highly lethal emerging infection.

Keywords: Nipah virus, innate immunity, adaptive immunity, pathogenesis, animal models, contra-measures

___

Corresponding author: Branka Horvat

Competing interests: No competing interests were disclosed.Grant information: The work was supported by LABEX ECOFECT (ANR-11-LABX-0048) of Lyon University within the “Investissements d’Avenir” program (ANR-11-IDEX-0007) conducted by the French National Research Agency (NRA) and by the Aviesan Sino-French agreement on Nipah virus study. RP is supported by a doctoral fellowship from the Direction Générale de l’Armement (DGA).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright:  © 2019 Pelissier R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Pelissier R, Iampietro M and Horvat B. Recent advances in the understanding of Nipah virus immunopathogenesis and anti-viral approaches [version 1; peer review: 3 approved]. F1000Research 2019, 8(F1000 Faculty Rev):1763 (https://doi.org/10.12688/f1000research.19975.1)

First published: 16 Oct 2019, 8(F1000 Faculty Rev):1763 (https://doi.org/10.12688/f1000research.19975.1)

Latest published: 16 Oct 2019, 8(F1000 Faculty Rev):1763 (https://doi.org/10.12688/f1000research.19975.1)

Keywords: Paramyxovirus; Nipah virus; Human; Bats; Immunopathology.

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#Cytokine Effects on the Entry of #Filovirus Envelope Pseudotyped Virus-Like Particles into Primary #Human #Macrophages (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Sep 23;11(10). pii: E889. doi: 10.3390/v11100889.

Cytokine Effects on the Entry of Filovirus Envelope Pseudotyped Virus-Like Particles into Primary Human Macrophages.

Stantchev TS1, Zack-Taylor A2, Mattson N3, Strebel K4, Broder CC5, Clouse KA6.

Author information: 1 Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA. tzanko.stantchev@fda.hhs.gov. 2 Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA. autumn.zack-taylor@fda.hhs.gov. 3 Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA. nicholas.mattson@fda.hhs.gov. 4 Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20814, USA. kstrebel@niaid.nih.gov. 5 Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD 20814, USA. christopher.broder@usuhs.edu. 6 Division of Biotechnology Review and Research 1 (DBRR1), Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA), Silver Spring, MD 20993, USA. kathleen.clouse@fda.hhs.gov.

 

Abstract

Macrophages are one of the first and also a major site of filovirus replication and, in addition, are a source of multiple cytokines, presumed to play a critical role in the pathogenesis of the viral infection. Some of these cytokines are known to induce macrophage phenotypic changes in vitro, but how macrophage polarization may affect the cell susceptibility to filovirus entry remains largely unstudied. We generated different macrophage subsets using cytokine pre-treatment and subsequently tested their ability to fuse with beta-lactamase containing virus-like particles (VLP), pseudotyped with the surface glycoprotein of Ebola virus (EBOV) or the glycoproteins of other clinically relevant filovirus species. We found that pre-incubation of primary human monocyte-derived macrophages (MDM) with interleukin-10 (IL-10) significantly enhanced filovirus entry into cells obtained from multiple healthy donors, and the IL-10 effect was preserved in the presence of pro-inflammatory cytokines found to be elevated during EBOV disease. In contrast, fusion of IL-10-treated macrophages with influenza hemagglutinin/neuraminidase pseudotyped VLPs was unchanged or slightly reduced. Importantly, our in vitro data showing enhanced virus entry are consistent with the correlation established between elevated serum IL-10 and increased mortality in filovirus infected patients and also reveal a novel mechanism that may account for the IL-10-mediated increase in filovirus pathogenicity.

KEYWORDS: Ebola virus (EBOV); cytokines; filoviruses; interleukin-10 (IL-10)

PMID: 31547585 DOI: 10.3390/v11100889

Keywords: Ebola; Filovirus; Cytokines; Immunopathology; Viral pathogenesis.

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