Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease

Britt, William J.

doi:10.1007/978-3-540-77349-8_23

Cited by 289 publications

(324 citation statements)

References 380 publications

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“…2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] …”

Section: Introductionmentioning

confidence: 99%

“…Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] and a prominent role of CD8 + T cells in preventing CMV replication and protecting against CMV disease has been established in the immunocompromised host [9].…”

Section: Introductionmentioning

confidence: 99%

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

et al. 2013

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Cytomegalovirus (CMV) infects a majority of the human population and establishes a lifelong persistence. CMV infection is usually asymptomatic but the virus carries pathogenic potential and causes severe disease in immunocompromised individuals. T-cell-mediated immunity plays an essential role in control of CMV infection and adoptive transfer of CMVspecific CD8 + T cells restores viral immunity in immunosuppressed patients but a role for CD4 + T cells remains elusive. Here, we analyzed in adoptive transfer studies the features and antiviral functions of virus-specific CD4 + T cells during primary murine CMV (MCMV) infection. MCMV-specific CD4 + T cells expanded upon MCMV infection and displayed an effector phenotype and function. Adoptive transfer of in vivo activated MCMV-specific CD4 + T cells to immune-compromised mice was protective during pathogenic MCMVinfection and IFN-γ was a crucial mediator of this protective capacity. Moreover, cotransfer of low doses of both MCMV-specific CD4 + T cells and CD8 + T cells synergized in control of lytic viral replication in immune-compromised mice. Our data reveal a pivotal antiviral role for virus-specific CD4 + T cells in protection from pathogenic CMV infection and provide evidence for their antiviral therapeutic potential. Keywords: Adoptive immunotherapy r CD4 + T cells r Cytomegalovirus infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunity to viral infections relies on effector mechanisms exerted by different components of the immune system. Despite the prominent roles of cytotoxic CD8 + T cells and neutralizing antibodies in controlling viral infections, there is growing evidence for an antiviral role of CD4 + helper T cells, not only in provision of help to other effector cells, but also in exertion of direct antiviral functions either by secretion of cytokines or exertion of cytotoxicity [1]. CD4 + T-cell-mediated protective immunity has been reported Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch for a number of viral infections [2][3][4][5]; however, the antiviral effector mechanisms exerted by CD4 + T cells in vivo have remained poorly characterized.Cytomegalovirus (CMV) is a β-herpes virus that infects a majority of the human population worldwide. After resolution of primary infection, this large DNA β-herpes virus establishes a life-long persistence in its host. CMV infection is usually clinically silent in healthy individuals. Nevertheless, CMV-infected immunosuppressed patients, such as hematopoietic BM or solid organ transplant recipients, suffer from CMV disease with potentially * These authors have contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] Results Expansion, activation, and phenotype of M25-specific CD4 + T cells during acute ...

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“…2013. 43: 2886-2895 Immunity to Infection 2887 severe clinical outcome [6]. Cellular immunity is important to control CMV infection [7,8] …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

et al. 2013

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“…HCMV infection is typically asymptomatic, but can cause severe disease or death in immunocompromised solid organ and hematopoietic stem cell transplant recipients. In addition, HCMV can infect the placenta and cross this barrier to infect developing fetuses, causing severe birth defects (2). Given the severity and importance of this disease, obtaining an effective vaccine is considered a public health priority (3).…”

mentioning

confidence: 99%

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Ciferri

Chandramouli

Donnarumma

et al. 2015

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

142

189

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Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and the leading viral cause of birth defects after congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are key targets of the human humoral response against HCMV and are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively. We expressed and characterized soluble forms of gH/gL, gH/gL/gO, and Pentamer. Mass spectrometry and mutagenesis analysis revealed that gL-Cys144 forms disulfide bonds with gO-Cys351 in gH/gL/gO and with UL128-Cys162 in the Pentamer. Notably, Pentamer harboring the UL128-Cys162Ser/gL-Cys144Ser mutations had impaired syncytia formation and reduced interference of HCMV entry into epithelial cells. Electron microscopy analysis showed that HCMV gH/gL resembles HSV gH/gL and that gO and UL128/UL130/UL131A bind to the same site at the gH/gL N terminus. These data are consistent with gH/gL/gO and Pentamer forming mutually exclusive cell entry complexes and reveal the overall location of gH/gL-, gH/gL/ gO-, and Pentamer-specific neutralizing antibody binding sites. Our results provide, to our knowledge, the first structural view of gH/gL/ gO and Pentamer supporting the development of vaccines and antibody therapeutics against HCMV.human cytomegalovirus | HCMV | Pentamer complex | gH/gL/gO | virus entry

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“…This implies transcription of epitope-encoding viral genes (Aiello et al 2008), translation of these transcripts to the respective antigenic proteins (Borza and Hutt-Fletcher 2002), and efficient antigen processing and epitope presentation (Britt 2008), all of which represent bottlenecks for MI to occur. We tried to address these points in our group over the past years and provided evidence strongly supporting the hypothesis that MI is driven by viral epitopes presented by latently infected host-tissue cells of non-hematopoietic origin (Seckert et al 2011;Torti et al 2011).…”

Section: T Cell Bmemory Inflation^as a Results Of Latency-associated Gmentioning

confidence: 99%

“…The virus will sporadically reactivate from latency in response to illdefined stimuli in the host, and the healthy host will asymptomatically shed low levels of virus to ensure spread. During primary infection, children will asymptomatically shed virus for months to years in their saliva and urine (Britt 2008). By contrast, it is not known how viral latency and persistence changes as the host ages.…”

Section: Regulation Of Latencymentioning

confidence: 99%

Recent advances in CMV tropism, latency, and diagnosis during aging

et al. 2017

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Human cytomegalovirus (CMV) is one of the largest viruses known to cause human diseases. Chronic CMV infection, as defined by anti-CMV IgG serology, increases with age and is highly prevalent in older adults. It has complex biology with significant immunologic and health consequences. This article aims to summarize research findings presented at the 6th International Workshop on CMV and Immunosenescence that relate to advances in the areas of CMV tropism, latency, CMV manipulation of cell metabolism, and T cell memory inflation, as well as novel diagnostic evaluation and translational research of chronic CMV infection in older adults. Information summarized here represents the current state of knowledge in these important fields. Investigators have also identified a number of areas that deserve further and more in-depth investigation, including building more precise parallels between mouse CMV (mCMV) and human CMV (HCMV) research. It is hoped that this article will also stimulate engaging discussion on strategies and direction to advance the science to the next level.

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Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease

Cited by 289 publications

References 380 publications

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Recent advances in CMV tropism, latency, and diagnosis during aging

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Manifestations of Human Cytomegalovirus Infection: Proposed Mechanisms of Acute and Chronic Disease

Cited by 289 publications

References 380 publications

Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

Adoptive transfer of cytomegalovirus‐specific effector CD4+T cells provides antiviral protection from murine CMV infection

Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Recent advances in CMV tropism, latency, and diagnosis during aging

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Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection

Adoptive transfer of cytomegalovirus‐specific effector CD4⁺T cells provides antiviral protection from murine CMV infection