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Viruses
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Role of Myeloid Cells in Viral Infections
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Role of Myeloid Cells in Viral Infections

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 35837

Special Issue Editors

Dr. Ravindra Gupta

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Guest Editor
University of Cambridge, Cambridge, UK
Interests: macrophages; HIV drug resistance; HIV virology; reservoirs
Dr. Petra Mlcochova

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Guest Editor
University of Cambridge, Cambridge, UK
Interests: macrophages; cell biology; biochemistry

Special Issue Information

Dear Colleagues,

Macrophages are relatively long-lived immune cells that exhibit broad tissue distribution and migration. Their functions are highly diverse and often tissue specific: for example, they are innate immune sentinels, antigen presenters, anti-tumour cells, tissue remodelers, as well as having roles in homeostasis e.g. the placenta, post inflammation resolution.

A number of prokaryotic pathogens are known to parasitize macrophages, including M. Tuberculosis and Leishmanial sp. Even though infection of macrophages has been shown for many viruses, such as dengue, zika, CMV or HIV, viral infection of macrophages is generally less well appreciated and relatively understudied. As an example of the importance of macrophages in HIV disease pathogenesis: it has been documented that some patients experience persistent HIV replication in the brain with clinical consequences. As the primary cell types infected by HIV in brain are myeloid cells such as microglia or perivascular macrophages, macrophages are indeed an important player in HIV infection under such circumstances.

Here we present a range of reviews addressing virus-macrophage interactions and associated implications for disease and therapeutic avenues.

Dr. Ravindra Gupta
Dr. Petra Mlcochova
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • macrophage
  • reservoir
  • SAMHD1
  • virus
  • HIV
  • replication
  • persistence

Published Papers (8 papers)

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Research

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9 pages, 738 KiB  
Article
Increased Monocyte Inflammatory Responses to Oxidized LDL Are Associated with Insulin Resistance in HIV-Infected Individuals on Suppressive Antiretroviral Therapy
by Brooks I. Mitchell, Elizabeth I. Laws, Dominic C. Chow, Ivo N. Sah Bandar, Louie Mar A. Gangcuangco, Cecilia M. Shikuma and Lishomwa C. Ndhlovu
Viruses 2020, 12(10), 1129; https://0-doi-org.brum.beds.ac.uk/10.3390/v12101129 - 05 Oct 2020
Cited by 2 | Viewed by 1813
Abstract
Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood [...] Read more.
Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1β, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1β and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1β and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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17 pages, 3918 KiB  
Article
The Nef Protein of the Macrophage Tropic HIV-1 Strain AD8 Counteracts Human BST-2/Tetherin
by Sebastian Giese, Scott P. Lawrence, Michela Mazzon, Bernadien M. Nijmeijer and Mark Marsh
Viruses 2020, 12(4), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040459 - 18 Apr 2020
Cited by 5 | Viewed by 2788
Abstract
Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) [...] Read more.
Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) group HIV type 1s (HIV-1s) are thought to rely exclusively on their Vpu proteins to overcome tetherin-mediated restriction of virus release. However, at least one M group HIV-1 strain, the macrophage-tropic primary AD8 isolate, is unable to express Vpu due to a mutation in its translation initiation codon. Here, using primary monocyte-derived macrophages (MDMs), we show that AD8 Nef protein can compensate for the absence of Vpu and restore virus release to wild type levels. We demonstrate that HIV-1 AD8 Nef reduces endogenous cell surface tetherin levels, physically separating it from the site of viral budding, thus preventing HIV retention. Mechanistically, AD8 Nef enhances internalisation of the long isoform of human tetherin, leading to perinuclear accumulation of the restriction factor. Finally, we show that Nef proteins from other HIV strains also display varying degrees of tetherin antagonism. Overall, we show that M group HIV-1s can use an accessory protein other than Vpu to antagonise human tetherin. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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Review

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16 pages, 256 KiB  
Review
Macrophage Tropism in Pathogenic HIV-1 and SIV Infections
by Matthew Moeser, Joshua R. Nielsen and Sarah B. Joseph
Viruses 2020, 12(10), 1077; https://0-doi-org.brum.beds.ac.uk/10.3390/v12101077 - 25 Sep 2020
Cited by 4 | Viewed by 2290
Abstract
Most myeloid lineage cells express the receptor and coreceptors that make them susceptible to infection by primate lentiviruses (SIVs and HIVs). However, macrophages are the only myeloid lineage cell commonly infected by SIVs and/or HIVs. The frequency of infected macrophages varies greatly across [...] Read more.
Most myeloid lineage cells express the receptor and coreceptors that make them susceptible to infection by primate lentiviruses (SIVs and HIVs). However, macrophages are the only myeloid lineage cell commonly infected by SIVs and/or HIVs. The frequency of infected macrophages varies greatly across specific host and virus combinations as well as disease states, with infection rates being greatest in pathogenic SIV infections of non-natural hosts (i.e., Asian nonhuman primates (Asian NHPs)) and late in untreated HIV-1 infection. In contrast, macrophages from natural SIV hosts (i.e., African NHPs) are largely resistant to infection due to entry and/or post-entry restriction mechanisms. These highly variable rates of macrophage infection may stem from differences in the host immune environment, entry and post-entry restriction mechanisms, the ability of a virus to adapt to efficiently infect macrophages, and the pleiotropic effects of macrophage-tropism including the ability to infect cells lacking CD4 and increased neutralization sensitivity. Questions remain about the relationship between rates of macrophage infection and viral pathogenesis, with some evidence suggesting that elevated levels of macrophage infection may contribute to greater pathogenesis in non-natural SIV hosts. Alternatively, extensive infection of macrophages may only emerge in the context of high viral loads and immunodeficiency, making it a symptom of highly pathogenic infections, not a primary driver of pathogenesis. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
16 pages, 3495 KiB  
Review
Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1
by Isabella A. T. M. Ferreira, J. Zachary Porterfield, Ravindra K. Gupta and Petra Mlcochova
Viruses 2020, 12(8), 839; https://0-doi-org.brum.beds.ac.uk/10.3390/v12080839 - 31 Jul 2020
Cited by 9 | Viewed by 4067
Abstract
Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and [...] Read more.
Macrophages are the first line of defence against invading pathogens. They play a crucial role in immunity but also in regeneration and homeostasis. Their remarkable plasticity in their phenotypes and function provides them with the ability to quickly respond to environmental changes and infection. Recent work shows that macrophages undergo cell cycle transition from a G0/terminally differentiated state to a G1 state. This G0-to-G1 transition presents a window of opportunity for HIV-1 infection. Macrophages are an important target for HIV-1 but express high levels of the deoxynucleotide-triphosphate hydrolase SAMHD1, which restricts viral DNA synthesis by decreasing levels of dNTPs. While the G0 state is non-permissive to HIV-1 infection, a G1 state is very permissive to HIV-1 infection. This is because macrophages in a G1 state switch off the antiviral restriction factor SAMHD1 by phosphorylation, thereby allowing productive HIV-1 infection. Here, we explore the macrophage cell cycle and the interplay between its regulation and permissivity to HIV-1 infection. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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17 pages, 1497 KiB  
Review
HIV-1 Persistence and Chronic Induction of Innate Immune Responses in Macrophages
by Hisashi Akiyama and Suryaram Gummuluru
Viruses 2020, 12(7), 711; https://0-doi-org.brum.beds.ac.uk/10.3390/v12070711 - 30 Jun 2020
Cited by 16 | Viewed by 3676
Abstract
A hallmark of HIV-1 infection is chronic inflammation, which plays a significant role in disease pathogenesis. Acute HIV infection induces robust inflammatory responses, which are insufficient to prevent or eliminate virus in mucosal tissues. While establishment of viral set-point is coincident with downregulation [...] Read more.
A hallmark of HIV-1 infection is chronic inflammation, which plays a significant role in disease pathogenesis. Acute HIV infection induces robust inflammatory responses, which are insufficient to prevent or eliminate virus in mucosal tissues. While establishment of viral set-point is coincident with downregulation of acute innate responses, systemic inflammatory responses persist during the course of chronic HIV infection. Since the introduction of combination antiviral therapy (cART), most HIV-1+ individuals can suppress viremia under detection levels for decades. However, chronic immune activation persists and has been postulated to cause HIV associated non-AIDS complications (HANA). Importantly, inflammatory cytokines and activation markers associated with macrophages are strongly and selectively correlated with the incidence of HIV-associated neurocognitive disorder (HAND), cardiovascular dysfunctions (CVD) and other HANA conditions. In this review, we discuss the roles of macrophages in facilitating viral persistence and contributing to generation of persistent inflammatory responses. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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17 pages, 2807 KiB  
Review
Macrophage Cell-Cell Interactions Promoting HIV-1 Infection
by Maeva Dupont and Quentin James Sattentau
Viruses 2020, 12(5), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/v12050492 - 28 Apr 2020
Cited by 22 | Viewed by 8877
Abstract
Many pathogens infect macrophages as part of their intracellular life cycle. This is particularly true for viruses, of which HIV-1 is one of the best studied. HIV-1 infection of macrophages has important consequences for viral persistence and pathogenesis, but the mechanisms of macrophage [...] Read more.
Many pathogens infect macrophages as part of their intracellular life cycle. This is particularly true for viruses, of which HIV-1 is one of the best studied. HIV-1 infection of macrophages has important consequences for viral persistence and pathogenesis, but the mechanisms of macrophage infection remain to be fully elucidated. Despite expressing viral entry receptors, macrophages are inefficiently infected by cell-free HIV-1 virions, whereas direct cell-cell spread is more efficient. Different modes of cell-cell spread have been described, including the uptake by macrophages of infected T cells and the fusion of infected T cells with macrophages, both leading to macrophage infection. Cell-cell spread can also transmit HIV-1 between macrophages and from macrophages to T cells. Here, we describe the current state of the field concerning the cell-cell spread of HIV-1 to and from macrophages, discuss mechanisms, and highlight potential in vivo relevance. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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28 pages, 2020 KiB  
Review
SAMHD1 Functions and Human Diseases
by Si’Ana A. Coggins, Bijan Mahboubi, Raymond F. Schinazi and Baek Kim
Viruses 2020, 12(4), 382; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040382 - 31 Mar 2020
Cited by 43 | Viewed by 8658
Abstract
Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been [...] Read more.
Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2′-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi–Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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8 pages, 296 KiB  
Review
Diverse and Unexpected Roles of Human Monocytes/Macrophages in the Immune Response to Influenza Virus
by Norbert J. Roberts, Jr.
Viruses 2020, 12(4), 379; https://0-doi-org.brum.beds.ac.uk/10.3390/v12040379 - 31 Mar 2020
Cited by 16 | Viewed by 3075
Abstract
Human monocytes/macrophages play a central role in the immune response and defense of the host from influenza virus infection. They classically act as antigen-presenting cells for lymphocytes in the context of an immune cell cluster. In that setting, however, monocytes/macrophages exhibit additional, unexpected, [...] Read more.
Human monocytes/macrophages play a central role in the immune response and defense of the host from influenza virus infection. They classically act as antigen-presenting cells for lymphocytes in the context of an immune cell cluster. In that setting, however, monocytes/macrophages exhibit additional, unexpected, roles. They are required for influenza virus infection of the lymphocytes in the cluster, and they are responsible for lymphocyte apoptosis via their synthesis and expression of the viral neuraminidase. Surprisingly, human alveolar macrophages, expected to be among the first cells to encounter the virus, are not susceptible to direct infection by a human influenza virus but can be infected when the virus is complexed with an antibody. Such monocyte/macrophage responses to influenza virus challenge should be considered part of a very complex but quite effective defense, since the common outcome is recovery of the host with development of immunity to the challenging strain of virus. Full article
(This article belongs to the Special Issue Role of Myeloid Cells in Viral Infections)
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