Overview of Human Cytomegalovirus Pathogenesis

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The establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase (PI3K) mediates viral entry into CD34 ϩ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to that in other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication-restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/ trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34 ϩ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34 ϩ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFR kinase (EGFRK) inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine interleukin 12 (IL-12) in HCMV-infected cells but not in mockinfected cells. These findings, along with our previous work with monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34 ϩ HPCs by HCMV.IMPORTANCE HCMV establishes lifelong persistence within the majority of the human population without causing overt pathogenesis in healthy individuals. Despite this, reactivation of HCMV from its latent reservoir in the bone marrow causes significant morbidity and mortality in immunologically compromised individuals, such as bone marrow and solid organ transplant patients. Lifelong persistent infection has also been linked with the development of various cardiovascular diseases in otherwise healthy individuals. Current HCMV therapeutics target lytic replication, but not the latent viral reservoir; thus, an understanding of the molecular basis for viral latency and persistence is paramount to controlling or eliminating HCMV infection. Here, we show that the viral signalosome activated by HCMV binding to its entry re-

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confidence: 99%

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 ⁺ Human Progenitor Cells

Kim

Collins-McMillen

Buehler

et al. 2017

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“…HCMV infection results in a wide range of pathogenic outcomes dependent upon the age and immune status of the host (2). Infection of immunocompetent hosts is usually asymptomatic or only mildly symptomatic (3,4); however, it can cause infectious mononucleosis, is a risk factor for the development of cardiovascular disease (5)(6)(7)(8)(9), and has been linked to certain types of cancers in otherwise healthy individuals (10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Collins-McMillen

Kim

Nogalski

et al. 2016

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Monocytes IMPORTANCEHematogenous dissemination of HCMV via infected monocytes is a crucial component of the viral survival strategy and is required for the establishment of persistent infection and for viral spread to additional hosts. Our system of infected primary human blood monocytes provides us with an opportunity to answer specific questions about viral spread and persistence in in vivo-relevant myeloid cells that cannot be addressed with the more traditionally used replication-permissive cells. Our goal in examining the mechanisms whereby HCMV reprograms infected monocytes to promote viral dissemination is to uncover new targets for therapeutic intervention that would disrupt key viral survival and persistence strategies. Because of this important role in maintaining survival of HCMV-infected monocytes, our new data on the role of Bcl-2 regulation during viral infection represents a promising molecular target for mitigating viral spread and persistence. H uman cytomegalovirus (HCMV) is a ubiquitous host-restricted betaherpesvirus that infects 60 to 90% of the population and persists for the lifetime of the infected individual (1). HCMV infection results in a wide range of pathogenic outcomes dependent upon the age and immune status of the host (2). Infection of immunocompetent hosts is usually asymptomatic or only mildly symptomatic (3, 4); however, it can cause infectious mononucleosis, is a risk factor for the development of cardiovascular disease (5-9), and has been linked to certain types of cancers in otherwise healthy individuals (10-15). In contrast, HCMV infection leads to significant morbidity and mortality in the immunocompromised. HCMV is an important opportunistic pathogen in AIDS patients (16)(17)(18)(19)(20), is a leading infectious cause of complications in transplant recipients (21-28), and causes severe neurological disease in congenitally infected neonates (29)(30)(31)(32)(33)(34).HCMV pathogenesis and disease result from viral spread to multiple organ sites following primary HCMV infection, a process which appears to be a critical step in the viral persistence strategy, as it allows for the establishment of lifelong persistence within the host, as well as for viral shedding and spread to additional hosts (1,35,36). Monocytes are the primary blood-borne targets for HCMV infection and are thought to be centrally involved in the hematogenous dissemination of the virus to target organ systems (37-41). We propose that HCMV reprograms the biology of infected monocytes, creating the ideal cell type to serve as "Trojan horses" to carry HCMV to target host organ sites and then to

“…he betaherpesvirus human cytomegalovirus (HCMV) affects 50 to 98% of people, causing severe symptoms in newborns and a lifetime latent infection that can be lethal in immunocompromised individuals (1). HCMV can also establish recurrent secondary infections after reactivation from latency (2).…”

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confidence: 99%

Characterization of Antibody Bipolar Bridging Mediated by the Human Cytomegalovirus Fc Receptor gp68

Ndjamen

Joshi

Fraser

et al. 2016

The human cytomegalovirus glycoprotein gp68 functions as an Fc receptor for host IgGs and can form antibody bipolar bridging (ABB) complexes in which gp68 binds the Fc region of an antigen-bound IgG. Here we show that gp68-mediated endocytosis transports ABB complexes into endosomes, after which the complex is routed to lysosomes, presumably for degradation. These results suggest gp68 contributes to evasion of IgG-mediated immune responses by mediating destruction of host IgG and viral antigens. The betaherpesvirus human cytomegalovirus (HCMV) affects 50 to 98% of people, causing severe symptoms in newborns and a lifetime latent infection that can be lethal in immunocompromised individuals (1). HCMV can also establish recurrent secondary infections after reactivation from latency (2). Immune evasion strategies of herpesviruses include expression of viral Fc receptors (Fc␥Rs) that bind host IgG to evade immune responses mediated by host Fc␥Rs (3-6). Viral Fc␥Rs can participate in antibody bipolar bridging (ABB), whereby an antibody simultaneously binds antigen via its fragment antigen-binding (Fab) arms and an Fc receptor using its Fc (7-9). While there is likely a large excess of nonviral IgG compared with antiviral IgG, the proximity of viral Fc␥Rs to Fc regions from IgGs bound to viral antigens on an infected cell could allow viral Fc␥Rs to preferentially bind antiviral IgGs. ABB protects virally infected cells from antibodyand complement-dependent neutralization (10), antibody-dependent cell-mediated cytotoxicity (11), and granulocyte attachment (12). The HCMV glycoproteins gp68, gp34, Toll-like receptor 12 (TLR12), and TLR13 act as Fc␥Rs to bind human IgG (3,6,13,14). Recent studies reported formation of ABB complexes with gp68 and with gp34 and demonstrated their functional importance by showing that cells infected with HCMV lacking gp68 and/or gp34 triggered stronger activation of the host Fc␥Rs and NK cells than cells infected with wildtype HCMV (15).In previous studies of ABB, we used cells expressing gE-gI, a herpes simplex virus 1 (HSV-1) Fc␥R, and gD, an HSV-1 cell surface antigen, to show that anti-gD IgGs formed ABB complexes with gE-gI and gD and that anti-gD IgG and gD were internalized in a gE-gI-dependent process, resulting in lysosomal localization of IgG and gD, but not gE-gI (8) (Fig. 1). Since gE-gI binds Fc at neutral/basic, but not acidic, pH (8, 16), these results were consistent with dissociation of IgG-antigen complexes from gE-gI upon trafficking to acidic intracellular vesicles. In contrast, the gp68-Fc interaction is broadly stable across acidic and basic pHs (17), suggesting a potentially different intracellular trafficking pathway if gp68, like gE-gI, can internalize ABB complexes.To investigate ABB mediated by HCMV gp68, we adapted the model system used to characterize gE-gI-mediated ABB (8). In the gE-gI studies, we transiently expressed gE-gI and gD in HeLa cells and then investigated the trafficking of gE-gI and gD under ABB and non-ABB conditions (8). We chose gD as the model ...