Common Threads in Persistent Viral Infections

Kane, Melissa; Golovkina, Tatyana V.

doi:10.1128/jvi.01905-09

Cited by 71 publications

(73 citation statements)

References 86 publications

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“…HCMV has evolved numerous mechanisms to block innate and adaptive immunity (Jenkins et al, 2008; Kane and Golovkina, 2010; Miller-Kittrell and Sparer, 2009; Wiertz et al, 2007). T cell-mediated cellular immunity is a key target for HCMV immune evasion strategies.…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus decreases constitutive transcription of MHC class II genes in mature Langerhans cells by reducing CIITA transcript levels

Lee

Wang

Hornell

et al. 2011

Molecular Immunology

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Human cytomegalovirus (HCMV) productively infects CD34+ progenitor-derived, mature Langerhans-type dendritic cells (matLC) and reduces surface expression of MHC class II complexes (MHC II) by increasing intracellular retention of these molecules. To determine whether HCMV also inhibits MHC II expression by other mechanisms, we assessed mRNA levels of the class II transcriptional regulator, CIITA, and several of its target genes in infected matLC. Levels of CIITA, HLA-DRA (DRA) and DRB transcripts, and new DR protein synthesis were compared in mock-infected and HCMV-infected cells by quantitative PCR and pulse-chase immunoprecipitation analyses, respectively. CIITA mRNA levels were significantly lower in HCMV-infected matLC as compared to mock-infected cells. When assessed in the presence of Actinomycin D, the stability of CIITA transcripts was not diminished by HCMV. Analysis of promoter-specific CIITA isoforms revealed that types I, III and IV all were decreased by HCMV, a result that differs from changes after incubation of these cells with lipopolysaccharide (LPS). Exposure to UV-inactivated virus failed to reduce CIITA mRNA levels, implicating de novo viral gene expression in this effect. HCMV-infected matLC also expressed lower levels of DR transcripts and reduced DR protein synthesis rates compared to mock-infected matLC. In summary, we demonstrate that HCMV infection of a human dendritic cell subset inhibits constitutive CIITA expression, most likely at the transcriptional level, resulting in reduced MHC II biosynthesis. We suggest this represents a new mechanism of modulation of mature LC by HCMV.

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Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus decreases constitutive transcription of MHC class II genes in mature Langerhans cells by reducing CIITA transcript levels

Lee

Wang

Hornell

et al. 2011

Molecular Immunology

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“…Strategies for preventing immune elimination include inhibition of antigen presentation or innate immune signaling, evasion of adaptive immunity through mutation of immune-dominant epitopes, and infection of an immune-privileged site (55)(56)(57). Therefore, potential immune-modulatory functions of NS1/2 must also be considered in addition to basic replicative functions.…”

Section: Discussionmentioning

confidence: 99%

A Single-Amino-Acid Change in Murine Norovirus NS1/2 Is Sufficient for Colonic Tropism and Persistence

Nice

Strong

McCune

et al. 2013

J Virol

117

172

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Human norovirus (HuNoV) is the major cause of acute nonbacterial gastroenteritis worldwide but has no clear animal reservoir. HuNoV can persist after the resolution of symptoms, and this persistence may be essential for viral maintenance within the population. Many strains of the related murine norovirus (MNV) also persist, providing a tractable animal model for studying norovirus (NoV) persistence. We have used recombinant cDNA clones of representative persistent (CR6) and nonpersistent (CW3) strains to identify a domain within the nonstructural gene NS1/2 that is necessary and sufficient for persistence. Furthermore, we found that a single change of aspartic acid to glutamic acid in CW3 NS1/2 was sufficient for persistence. This same conservative change also caused increased growth of CW3 in the proximal colon, which we found to be a major tissue reservoir of MNV persistence, suggesting that NS1/2 determines viral tropism that is necessary for persistence. These findings represent the first identified function for NoV NS1/2 during infection and establish a novel model system for the study of enteric viral persistence.

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“…Viruses that induce chronic infections employ a range of strategies for evading the host immune system, but one mechanism has emerged as a common theme: induction of IL-10 (Blackburn and Wherry, 2007; Kane and Golovkina, 2010). IL-10 is a pleiotropic cytokine that can effectively attenuate immune responses through the suppression of inflammatory cytokines and inhibition of T cell proliferation (Mosser and Zhang, 2008).…”

mentioning

confidence: 99%

Antibodies to human IL-10 neutralize ebvIL-10-mediated cytokine suppression but have no effect on cmvIL-10 activity

Brodeur

Spencer

2010

Virus Research

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Interleukin-10 is a pivotal determinant of virus clearance or persistence. Two human herpesviruses, Epstein–Barr virus (EBV) and human cytomegalovirus (HCMV) are unique among persistent viruses because they not only trigger production of host IL-10, but both viruses also encode homologs of IL-10 that are expressed during infection. Because anti-human IL-10 antibodies have diagnostic value and therapeutic potential for many chronic infections, cross-reactivity with ebvIL-10 and cmvIL-10 was evaluated in this study. Six of seven anti-hIL-10 antibodies tested recognized ebvIL-10 and neutralized its immuno-suppressive activity. In contrast, cmvIL-10 was neither recognized nor neutralized by any anti-human IL-10 antibody. These findings demonstrate that IL-10-neutralizing treatments in HCMV-or EBV-infected patients may require consideration of the contribution of viral IL-10 to disease pathology.

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Common Threads in Persistent Viral Infections

Cited by 71 publications

References 86 publications

Human cytomegalovirus decreases constitutive transcription of MHC class II genes in mature Langerhans cells by reducing CIITA transcript levels

Human cytomegalovirus decreases constitutive transcription of MHC class II genes in mature Langerhans cells by reducing CIITA transcript levels

A Single-Amino-Acid Change in Murine Norovirus NS1/2 Is Sufficient for Colonic Tropism and Persistence

Antibodies to human IL-10 neutralize ebvIL-10-mediated cytokine suppression but have no effect on cmvIL-10 activity

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