Review

17 pages, 953 KiB

Open AccessReview

Pathogen at the Gates: Human Cytomegalovirus Entry and Cell Tropism

by Christopher C. Nguyen and Jeremy P. Kamil

Viruses 2018, 10(12), 704; https://doi.org/10.3390/v10120704 - 11 Dec 2018

Cited by 96 | Viewed by 8275

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that it infects. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRα) were identified as receptors, respectively, for the trimeric [...] Read more.

The past few years have brought substantial progress toward understanding how human cytomegalovirus (HCMV) enters the remarkably wide spectrum of cell types and tissues that it infects. Neuropilin-2 and platelet-derived growth factor receptor alpha (PDGFRα) were identified as receptors, respectively, for the trimeric and pentameric glycoprotein H/glycoprotein L (gH/gL) complexes that in large part govern HCMV cell tropism, while CD90 and CD147 were also found to play roles during entry. X-ray crystal structures for the proximal viral fusogen, glycoprotein B (gB), and for the pentameric gH/gL complex (pentamer) have been solved. A novel virion gH complex consisting of gH bound to UL116 instead of gL was described, and findings supporting the existence of a stable complex between gH/gL and gB were reported. Additional work indicates that the pentamer promotes a mode of cell-associated spread that resists antibody neutralization, as opposed to the trimeric gH/gL complex (trimer), which appears to be broadly required for the infectivity of cell-free virions. Finally, viral factors such as UL148 and US16 were identified that can influence the incorporation of the alternative gH/gL complexes into virions. We will review these advances and their implications for understanding HCMV entry and cell tropism. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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18 pages, 1108 KiB

Open AccessReview

HCMV Infection and Apoptosis: How Do Monocytes Survive HCMV Infection?

by Donna Collins-McMillen, Liudmila Chesnokova, Byeong-Jae Lee, Heather L. Fulkerson, Reynell Brooks, Bailey S. Mosher and Andrew D. Yurochko

Viruses 2018, 10(10), 533; https://doi.org/10.3390/v10100533 - 29 Sep 2018

Cited by 26 | Viewed by 4401

Abstract

Human cytomegalovirus (HCMV) infection of peripheral blood monocytes plays a key role in the hematogenous dissemination of the virus to multiple organ systems following primary infection or reactivation of latent virus in the bone marrow. Monocytes have a short life span of 1–3 [...] Read more.

Human cytomegalovirus (HCMV) infection of peripheral blood monocytes plays a key role in the hematogenous dissemination of the virus to multiple organ systems following primary infection or reactivation of latent virus in the bone marrow. Monocytes have a short life span of 1–3 days in circulation; thus, HCMV must alter their survival and differentiation to utilize these cells and their differentiated counterparts—macrophages—for dissemination and long term viral persistence. Because monocytes are not initially permissive for viral gene expression and replication, HCMV must control host-derived factors early during infection to prevent apoptosis or programmed cell death prior to viral induced differentiation into naturally long-lived macrophages. This review provides a short overview of HCMV infection of monocytes and describes how HCMV has evolved to utilize host cell anti-apoptotic pathways to allow infected monocytes to bridge the 48–72 h viability gate so that differentiation into a long term stable mature cell can occur. Because viral gene expression is delayed in monocytes following initial infection and only occurs (begins around two to three weeks post infection in our model) following what appears to be complete differentiation into mature macrophages or dendritic cells, or both; virally-encoded anti-apoptotic gene products cannot initially control long term infected cell survival. Anti-apoptotic viral genes are discussed in the second section of this review and we argue they would play an important role in long term macrophage or dendritic cell survival following infection-induced differentiation. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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13 pages, 1090 KiB

Open AccessReview

The Interplay between Human Cytomegalovirus and Pathogen Recognition Receptor Signaling

by Mariana Marques, Ana Rita Ferreira and Daniela Ribeiro

Viruses 2018, 10(10), 514; https://doi.org/10.3390/v10100514 - 20 Sep 2018

Cited by 17 | Viewed by 5079

Abstract

The cellular antiviral innate immune response is triggered upon recognition of specific viral components by a set of the host’s cytoplasmic or membrane-bound receptors. This interaction induces specific signaling cascades that culminate with the production of interferons and the expression of interferon-stimulated genes [...] Read more.

The cellular antiviral innate immune response is triggered upon recognition of specific viral components by a set of the host’s cytoplasmic or membrane-bound receptors. This interaction induces specific signaling cascades that culminate with the production of interferons and the expression of interferon-stimulated genes and pro-inflammatory cytokines that act as antiviral factors, suppressing viral replication and restricting infection. Here, we review and discuss the different mechanisms by which each of these receptors is able to recognize and signal infection by the human cytomegalovirus (HCMV), an important human pathogen mainly associated with severe brain defects in newborns and disabilities in immunocompromised individuals. We further present and discuss the many sophisticated strategies developed by HCMV to evade these different signaling mechanisms and counteract the cellular antiviral response, in order to support cell viability and sustain its slow replication cycle. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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18 pages, 1116 KiB

Open AccessReview

Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

by Christopher M. Goodwin, Jessica H. Ciesla and Joshua Munger

Viruses 2018, 10(9), 447; https://doi.org/10.3390/v10090447 - 21 Aug 2018

Cited by 28 | Viewed by 4948

Abstract

As essential components of the host’s innate immune response, NFκB and interferon signaling are critical determinants of the outcome of infection. Over the past 25 years, numerous Human Cytomegalovirus (HCMV) genes have been identified that antagonize or modulate the signaling of these pathways. [...] Read more.

As essential components of the host’s innate immune response, NFκB and interferon signaling are critical determinants of the outcome of infection. Over the past 25 years, numerous Human Cytomegalovirus (HCMV) genes have been identified that antagonize or modulate the signaling of these pathways. Here we review the biology of the HCMV factors that alter NFκB and interferon signaling, including what is currently known about how these viral genes contribute to infection and persistence, as well as the major outstanding questions that remain. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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25 pages, 12707 KiB

Open AccessReview

US28: HCMV’s Swiss Army Knife

by Benjamin A. Krishna, William E. Miller and Christine M. O’Connor

Viruses 2018, 10(8), 445; https://doi.org/10.3390/v10080445 - 20 Aug 2018

Cited by 43 | Viewed by 6615

Abstract

US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed [...] Read more.

US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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27 pages, 1947 KiB

Open AccessReview

Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation

by Donna Collins-McMillen, Jason Buehler, Megan Peppenelli and Felicia Goodrum

Viruses 2018, 10(8), 444; https://doi.org/10.3390/v10080444 - 20 Aug 2018

Cited by 84 | Viewed by 9412

Abstract

Human cytomegalovirus (HCMV) is a beta herpesvirus that establishes a life-long persistence in the host, like all herpesviruses, by way of a latent infection. During latency, viral genomes are maintained in a quieted state. Virus replication can be reactivated from latency in response [...] Read more.

Human cytomegalovirus (HCMV) is a beta herpesvirus that establishes a life-long persistence in the host, like all herpesviruses, by way of a latent infection. During latency, viral genomes are maintained in a quieted state. Virus replication can be reactivated from latency in response to changes in cellular signaling caused by stress or differentiation. The past decade has brought great insights into the molecular basis of HCMV latency. Here, we review the complex persistence of HCMV with consideration of latent reservoirs, viral determinants and their host interactions, and host signaling and the control of cellular and viral gene expression that contributes to the establishment of and reactivation from latency. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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16 pages, 1697 KiB

Open AccessReview

The Human Cytomegalovirus, from Oncomodulation to Oncogenesis

by Georges Herbein

Viruses 2018, 10(8), 408; https://doi.org/10.3390/v10080408 - 03 Aug 2018

Cited by 104 | Viewed by 7363

Abstract

Besides its well-described impact in immunosuppressed patients, the role of human cytomegalovirus (HCMV) in the pathogenesis of cancer has been more recently investigated. In cancer, HCMV could favor the progression and the spread of the tumor, a paradigm named oncomodulation. Although oncomodulation could [...] Read more.

Besides its well-described impact in immunosuppressed patients, the role of human cytomegalovirus (HCMV) in the pathogenesis of cancer has been more recently investigated. In cancer, HCMV could favor the progression and the spread of the tumor, a paradigm named oncomodulation. Although oncomodulation could account for part of the protumoral effect of HCMV, it might not explain the whole impact of HCMV infection on the tumor and the tumoral microenvironment. On the contrary cases have been reported where HCMV infection slows down the progression and the spread of the tumor. In addition, HCMV proteins have oncogenic properties per se, HCMV activates pro-oncogenic pathways in infected cells, and recently the direct transformation of cells following HCMV infection has been described, which gave rise to tumors when injected in mice. Thus, beyond the oncomodulation model, this review will assess the direct transforming role of HMCV-infected cells and the potential classification of HCMV as an oncovirus. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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18 pages, 473 KiB

Open AccessReview

Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection

by William J. Britt

Viruses 2018, 10(8), 405; https://doi.org/10.3390/v10080405 - 03 Aug 2018

Cited by 76 | Viewed by 7744

Abstract

Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It [...] Read more.

Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar. These findings from natural history studies have important implications for the design, development, and testing of prophylactic vaccines and biologics for this perinatal infection. This brief overview will provide a discussion of existing data from human natural history studies and animal models of congenital HCMV infections that have described the role of maternal immunity in the natural history of this perinatal infection. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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14 pages, 5396 KiB

Open AccessReview

There Is Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

by Joseph W. Jackson and Tim Sparer

Viruses 2018, 10(7), 383; https://doi.org/10.3390/v10070383 - 20 Jul 2018

Cited by 38 | Viewed by 20692

Abstract

Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed [...] Read more.

Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner’s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell-free virus. Also, in vivo CMVs infect new cells via cell-to-cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV’s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models. Full article

(This article belongs to the Special Issue Recent Advances in Cytomegalovirus Research)

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