Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line

Koldehoff, Michael; Lindemann, Monika; Roß, Stefan; Elmaagacli, Ahmet H.

doi:10.1371/journal.pone.0191482

Cited by 9 publications

(29 citation statements)

References 40 publications

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“…Since HCMV can modulate interferon gamma signaling (19,23), this may be one way of decreasing promoter IV CIITA transcripts. Coculturing infected Kasumi-1 cells with uninfected peripheral blood mononuclear cells resulted in an increase in HLA-DR transcript levels, illustrating the complexity of the HCMV-mediated regulation of MHC class II under different conditions (59). Importantly, our results focus on the endogenous regulation of MHC class II and show that HCMV downregulates the expression of CIITA by decreasing transcription from promoter III, resulting in decreased HLA-DR␣ transcripts and MHC class II surface expression.…”

Section: Discussionmentioning

confidence: 65%

Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

Sandhu

Buchkovich

2020

J Virol

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that encodes many proteins to modulate the host immune response. Extensive efforts have led to the elucidation of multiple strategies employed by HCMV to effectively block NK cell targeting of virus-infected cells and the major histocompatibility complex (MHC) class I-primed CD8+ T cell response. However, viral regulation of the MHC class II-mediated CD4+ T cell response is understudied in endogenous MHC class II-expressing cells, largely because the popular cell culture systems utilized for studying HCMV do not endogenously express MHC class II. Of the many cell types infected by HCMV in the host, myeloid cells, such as monocytes, are of particular importance due to their role in latency and subsequent dissemination throughout the host. We investigated the impact of HCMV infection on MHC class II in Kasumi-3 cells, a myeloid-progenitor cell line that endogenously expresses the MHC class II gene, HLA-DR. We observed a significant reduction in the expression of surface and total HLA-DR at 72 h postinfection (hpi) and 120 hpi in infected cells. The decrease in HLA-DR expression was independent of the expression of previously described viral genes that regulate the MHC class II complex or the unique short (US) region of HCMV, a region expressing many immunomodulatory genes. The altered surface level of HLA-DR was not a result of increased endocytosis and degradation but was a result of a reduction in HLA-DR transcripts due to a decrease in the expression of the class II transactivator (CIITA). IMPORTANCE Human cytomegalovirus (HCMV) is an opportunistic herpesvirus that is asymptomatic for healthy individuals but that can lead to severe pathology in patients with congenital infections and immunosuppressed patients. Thus, it is important to understand the modulation of the immune response by HCMV, which is understudied in the context of endogenous MHC class II regulation. Using Kasumi-3 cells as a myeloid progenitor cell model endogenously expressing MHC class II (HLA-DR), this study shows that HCMV decreases the expression of HLA-DR in infected cells by reducing the transcription of HLA-DR transcripts early during infection independently of the expression of previously implicated genes. This is an important finding, as it highlights a mechanism of immune evasion utilized by HCMV to decrease the expression of MHC class II in a relevant cell system that endogenously expresses the MHC class II complex.

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Section: Discussionmentioning

confidence: 65%

Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

Sandhu

Buchkovich

2020

J Virol

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“…Although somewhat controversial, a number of human clinical studies have demonstrated an association between HCMV reactivation following bone marrow transplantation and reduced relapse rates of leukemias and lymphomas [89][90][91]. Multiple mechanisms are thought to be at play in these cases related to the known effects of CMV on activation of NK cells [92], CD8 + T cells and γδ T cells [89] as well as the potential for both direct and immunostimulatory oncolytic effects [93].…”

Section: Cmv-specific Cd8 + T Cells: the Link Between CMV Infection Amentioning

confidence: 99%

The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Heath

Grant

2020

Cells

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Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.

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“…In healthy individuals, HCMV infection is generally asymptomatic, although HCMV can cause acute infectious mononucleosis (2,3) and has also been linked to chronic inflammatory diseases, such as atherosclerosis, and cancers, including glioblastoma and colon cancer (4,5). In contrast, HCMV infection of immunocompromised individuals, including AIDS patients and transplant recipients, causes severe morbidity and mortality (6)(7)(8). HCMV is also the most common congenital infection occurring in approximately 20,000 to 30,000 infants each year in the United States, with approximately 10 to 15% of infected newborns developing permanent neurological abnormalities (9).…”

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confidence: 99%

Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt

Mahmud

Miller

Altman

et al. 2020

J Virol

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Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality among immunocompromised and immunonaive individuals. HCMV-induced signaling initiated during viral entry stimulates a rapid noncanonical activation of Akt to drive the differentiation of short-lived monocytes into long-lived macrophages, which is essential for viral dissemination and persistence. We found that HCMV glycoproteins gB and gH directly bind and activate cellular epidermal growth factor receptor (EGFR) and integrin β1, respectively, to reshape canonical Akt signaling within monocytes. The remodeling of the Akt signaling network was due to the recruitment of non-traditional Akt activators to either the gB- or gH-generated receptor signaling complexes. Phosphoinositide 3-kinase (PI3K) comprised of the p110β catalytic subunit was recruited to the gB/EGFR complex despite p110δ being the primary PI3K isoform found within monocytes. Concomitantly, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) was recruited to the gH/integrin β1 complex, which is critical to aberrant Akt activation as SHIP1 diverts PI3K signaling towards a noncanonical pathway. Although integrin β1 was required for SHIP1 recruitment, gB-activated EGFR mediated SHIP1 activation, underscoring the importance of the interplay between gB- and gH-mediated signaling to the unique activation of Akt during HCMV infection. Indeed, SHIP1 activation mediated the increased expression of Mcl-1 and HSP27, two Akt-dependent anti-apoptotic proteins specifically upregulated during HCMV infection but not during growth factor treatment. Overall, our data indicate that HCMV glycoproteins gB and gH work in concert to initiate a HCMV-specific signalsome responsible for the atypical activation of Akt required for infected monocyte survival and ultimately viral persistence. IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic throughout the world regardless of socio-economic conditions and geographic locations with a seroprevalence reaching up to 100% in some developing countries. Although asymptomatic in healthy individuals, HCMV can cause severe multi-organ disease in immunocompromised or immunonaive patients. HCMV disease is a direct consequence of monocyte-mediated systematic spread of the virus following infection. Because monocytes are short-lived cells, HCMV must subvert the natural short lifespan of these blood cells by inducing a distinct activation of Akt, a serine/theonine-protein kinase. In this work, we demonstrate that HCMV glycoproteins gB and gH work in tandem to reroute classical host cellular receptor signaling to aberrantly activate Akt and drive survival of infected monocytes. Deciphering how HCMV modulates the cellular pathway to induce monocyte survival is important to develop a new class of anti-HCMV drugs that could target and prevent spread of the virus by eliminating infected monocytes.

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Cytomegalovirus induces HLA-class-II-restricted alloreactivity in an acute myeloid leukemia cell line

Cited by 9 publications

References 40 publications

Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

Human Cytomegalovirus Decreases Major Histocompatibility Complex Class II by Regulating Class II Transactivator Transcript Levels in a Myeloid Cell Line

The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt

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