Cytomegalovirus and transcriptional down-regulation of major histocompatibility complex class II expression

Miller, Daniel M.; Cebulla, Colleen M.; Rahill, Brian M.; Sedmak, Daniel D.

doi:10.1006/smim.2001.0291

Cited by 18 publications

(10 citation statements)

References 76 publications

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“…The recent suggestion that U373 cells are somehow not appropriate for studies of HCMV's effects on class II proteins (33a) fails to recognize several observations: (i) that HCMV infects glial cells in vivo (44) and causes frequent neurologic damage in children and (ii) that glial cells naturally express low levels of class II proteins, can present antigens to CD4 ϩ T cells (40), and can be readily induced to express higher levels of class II. Moreover, it must also be kept in mind that US2 does not act in isolation; HCMV infection leads to the expression of other viral proteins that can inhibit the class II pathway, including US3 that causes mislocalization of class II complexes preventing peptide loading (Hegde et al, unpublished), and unidentified inhibitors of class II transcription (30,31).…”

Section: Discussionmentioning

confidence: 99%

Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation

Chevalier

Daniels

Johnson

2002

J Virol

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Human cytomegalovirus (HCMV) glycoprotein US2 causes degradation of major histocompatibility complex (MHC) class I heavy-chain (HC), class II DR-␣ and DM-␣ proteins, and HFE, a nonclassical MHC protein.In US2-expressing cells, MHC proteins present in the endoplasmic reticulum (ER) are degraded by cytosolic proteasomes. It appears that US2 binding triggers a normal cellular pathway by which misfolded or aberrant proteins are translocated from the ER to cytoplasmic proteasomes. To better understand how US2 binds MHC proteins and causes their degradation, we constructed a panel of US2 mutants. Mutants truncated from the N terminus as far as residue 40 or from the C terminus to amino acid 140 could bind to class I and class II proteins. Nevertheless, mutants lacking just the cytosolic tail (residues 187 to 199) were unable to cause degradation of both class I and II proteins. Chimeric proteins were constructed in which US2 sequences were replaced with homologous sequences from US3, an HCMV glycoprotein that can also bind to class I and II proteins. One of these US2/US3 chimeras bound to class II but not to class I, and a second bound class I HC better than wild-type US2. Therefore, US2 residues involved in the binding to MHC class I differ subtly from those involved in binding to class II proteins. Moreover, our results demonstrate that the binding of US2 to class I and II proteins is not sufficient to cause degradation of MHC proteins. The cytosolic tail of US2 and certain US2 lumenal sequences, which are not involved in binding to MHC proteins, are required for degradation. Our results are consistent with the hypothesis that US2 couples MHC proteins to components of the ER degradation pathway, enormously increasing the rate of degradation of MHC proteins.Human cytomegalovirus (HCMV) is a betaherpesvirus that can cause serious disease in children and patients who are immunosuppressed or immunodeficient. HCMV can infect diverse cell types, including epithelial, glial, and endothelial cells, fibroblasts, and monocytes/macrophages, and generally replicates slowly in most cells. The virus establishes a latent state in monocytes/macrophages (37). Periodic reactivation and replication occurs in the face of robust, fully primed host immunity. HCMV survives and spreads to other hosts, in part, by inhibiting recognition by T lymphocytes and natural killer cells (reviewed in references 22, 23, and 41).The S component of the HCMV genome includes a region, US2-US11, that encodes eight membrane glycoproteins of similar size and showing limited homology one to another (20, 24;

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Section: Discussionmentioning

confidence: 99%

Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation

Chevalier

Daniels

Johnson

2002

J Virol

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“…HCMV relies on multiple strategies to evade host defenses, including inhibition of immune cell activation and cytokine/chemokine secretion (40)(41)(42)(43)(44)(45). Because monocytes are designed to destroy invading pathogens, we suggest that HCMV may use this identified trafficking pathway as a previously unidentified evasion mechanism to allow productive infection.…”

Section: Discussionmentioning

confidence: 97%

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Kim

Collins-McMillen

Caposio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We initiated experiments to examine the infection of monocytes postentry. New data show that human cytomegalovirus (HCMV) DNA is detected in the nucleus beginning only at 3 d postinfection in monocytes, compared with 30 min postinfection in fibroblasts and endothelial cells, suggesting that HCMV nuclear translocation in monocytes is distinct from that seen in other cell types. We now show that HCMV is initially retained in early endosomes and then moves sequentially to the trans-Golgi network (TGN) and recycling endosomes before nuclear translocation. HCMV is retained initially as a mature particle before deenvelopment in recycling endosomes. Disruption of the TGN significantly reduced nuclear translocation of viral DNA, and HCMV nuclear translocation in infected monocytes was observed only when correct gH/gL/UL128-131/integrin/c-Src signaling occurred. Taken together, our findings show that viral binding of the gH/gL/UL128-131 complex to integrins and the ensuing c-Src signaling drive a unique nuclear translocation pattern that promotes productive infection and avoids viral degradation, suggesting that it represents an additional viral evasion/survival strategy.monocytes | viral trafficking | gH/gL/UL128-131 complex | integrins | nuclear translocation pathway H uman cytomegalovirus (HCMV) infection usually results in an asymptomatic lifelong persistent infection in healthy individuals after primary infection (1, 2). Although HCMV infection rarely causes disease in immunocompetent individuals, it can cause severe/ fatal disease in immunocompromised patients, such as congenitally infected neonates, patients with AIDS, and transplant recipients (3-6). HCMV infection is also associated with the development of cardiovascular diseases, including atherosclerosis, restenosis, and transplant vascular sclerosis, as well as some cancers (7-10). This wide range of pathological complications results from viral spread to multiple organs and the broad cellular tropism displayed by HCMV following infection (11).Monocytes are a primary site of persistent HCMV infection, and HCMV-infected monocytes are believed to play a key role in the hematogenous dissemination of the virus to target organs following primary infection (12). For HCMV to infect primary monocytes, it must overcome several biological barriers to successfully mediate viral spread and persistence. For example, monocytes do not initially support de novo HCMV gene expression and viral replication (13), and they have a lifespan of only 1-3 d in circulation under normal homeostatic conditions (14, 15). Understanding how HCMV overcomes these biological barriers following infection may provide clues to the underlying causes of HCMV pathogenesis and persistence. Our laboratory has provided molecular evidence for how HCMV evolved to deal with these biological barriers (16)(17)(18)(19)(20)(21)(22).We have shown that the biological changes in HCMV-infected monocytes are triggered by the binding of gB to EGFR (19) and binding of the gH/gL/UL128-131 complex to β1 and β3 integri...

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“…This is achieved by modulation of the expression of Janus kinase 1 (JAK1) and repression of Class II transactivator (CIITA) mRNA. In addition, US2 can direct HLA-DR and HLA-DM to the cytosol where they are degraded [52].…”

Section: The Memory Cd8+ and Cd4+ T Cell Response To Hcmv In Long-termentioning

confidence: 99%

Dynamics of T cell memory in human cytomegalovirus infection

Waller

Day

Sissons

et al. 2008

Med Microbiol Immunol

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Primary human cytomegalovirus (HCMV) infection of an immunocompetent individual leads to the generation of a robust CD4+ and CD8+ T cell response which subsequently controls viral replication. HCMV is never cleared from the host and enters into latency with periodic reactivation and viral replication, which is controlled by reactivation of the memory T cells. In this article, we discuss the magnitude, phenotype and clonality of the T cell response following primary HCMV infection, the selection of responding T cells into the long-term memory pool and maintenance of this memory T cell population in the face of a latent/persistent infection. The article also considers the eVect that this long-term surveillance of HCMV has on the T cell memory phenotype, their diVerentiation, function and the associated concepts of T cell memory inXation and immunosenescence.

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Cytomegalovirus and transcriptional down-regulation of major histocompatibility complex class II expression

Cited by 18 publications

References 76 publications

Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation

Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation

Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes

Dynamics of T cell memory in human cytomegalovirus infection

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