A ?-herpesvirus immune evasion gene allows tumor cellsin vivo to escape attack by cytotoxic T cells specific for a tumor epitope

Rice, Jason; Lima, Brigitte D. de; Stevenson, Freda K.; Stevenson, Philip G.

doi:10.1002/1521-4141(200212)32:12<3481::aid-immu3481>3.0.co;2-j

Cited by 23 publications

(12 citation statements)

References 24 publications

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“…The myxoma virus protein M-T7, 35-kDa poxviral vCKBP, or murine gammaherpesvirus 68 vCKBP M3 immunomodulatory activity has been demonstrated in models of chronic transplant vasculopathy and airway or skin inflammation (8,19,24,30,31,37). Different strategies that interfere with chemokine-GAG interactions for therapeutic benefit may be explored.…”

Section: Discussionmentioning

confidence: 99%

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

Ruiz-Argüello

Smith

Campanella

et al. 2008

J Virol

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Poxviruses encode a number of secreted virulence factors that modulate the host immune response. The vaccinia virus A41 protein is an immunomodulatory protein with amino acid sequence similarity to the 35-kDa chemokine binding protein, but the host immune molecules targeted by A41 have not been identified. We report here that the vaccinia virus A41 ortholog encoded by ectromelia virus, a poxvirus pathogen of mice, named E163 in the ectromelia virus Naval strain, is a secreted 31-kDa glycoprotein that selectively binds a limited number of CC and CXC chemokines with high affinity. A detailed characterization of the interaction of ectromelia virus E163 with mutant forms of the chemokines CXCL10 and CXCL12␣ indicated that E163 binds to the glycosaminoglycan binding site of the chemokines. This suggests that E163 inhibits the interaction of chemokines with glycosaminoglycans and provides a mechanism by which E163 prevents chemokine-induced leukocyte migration to the sites of infection. In addition to interacting with chemokines, E163 can interact with high affinity with glycosaminoglycan molecules, enabling E163 to attach to cell surfaces and to remain in the vicinity of the sites of viral infection. These findings identify E163 as a new chemokine binding protein in poxviruses and provide a molecular mechanism for the immunomodulatory activity previously reported for the vaccinia virus A41 ortholog. The results reported here also suggest that the cell surface and extracellular matrix are important targeting sites for secreted poxvirus immune modulators.

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Section: Discussionmentioning

confidence: 99%

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

Ruiz-Argüello

Smith

Campanella

et al. 2008

J Virol

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“…In vivo gammaherpesvirus latency is almost invariably accompanied by lytic gene expression [30], and while lytic viral replication probably has little impact on latency in immunocompetent hosts [41,42,50], lytic gene expression may have a significant effect. For example, the MHV-68-secreted chemokine-binding protein M3 provides bystander protection against CD8 + T cell recognition [51]. If gammaherpesviruses sacrifice lytically infected cells to protect latent genomes, CD4 + T cells could limit latency by inhibiting viral lytic gene expression [26] to make latent antigen-specific CD8 + T cells more effective.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺ T cells specific for a model latency‐associated antigen fail to control a gammaherpesvirus in vivo

et al. 2006

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CD4+ T cells play a major role in containing herpesvirus infections. However, their cellular targets remain poorly defined. In vitro CD4+ T cells have been reported to kill B cells that harbor a latent gammaherpesvirus. We used the B cell‐tropic murine gammaherpesvirus‐68 (MHV‐68) to test whether this also occurred in vivo. MHV‐68 that expressed cytoplasmic ovalbumin (OVA) in tandem with its episome maintenance protein, ORF73, stimulated CD8+ T cells specific for the H2‐Kb‐restricted OVA epitope SIINFEKL and was rapidly eliminated from C57BL/6 (H2b) mice. However, the same virus failed to stimulate CD4+ T cells specific for the I‐Ad/I‐Ab‐restricted OVA323–339 epitope. We overcame any barrier to the MHC class II‐restricted presentation of an endogenous epitope by substituting OVA323–339 for the CLIP peptide of the invariant chain (ORF73‐IRES‐Ii‐OVA), again expressed in tandem with ORF73. This virus presented OVA323–339 but showed little or no latency deficit in either BALB/c (H2d) or C57BL/6 mice. Latent antigen‐specific CD4+ T cells therefore either failed to recognize key virus‐infected cell populations in vivo or lacked the effector functions required to control them.

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“…ϩ -T-cell evasion (7,32) and may compensate for the lack of a K5, although exactly where it fits into in vivo pathogenesis remains controversial (41). M3 may also overlap in function with the KSHV vMIPs (26).…”

mentioning

confidence: 99%

An InternalRibosome Entry Site Directs Translation of the Murine Gammaherpesvirus68 MK3 Open ReadingFrame

Coleman

Brierley

Stevenson

2003

J Virol

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The gammaherpesviruses characteristically drive the proliferation of latently infected lymphocytes. The murine gammaherpesvirus 68 (MHV-68) MK3 protein contributes to this process in vivo by evading CD8؉ -T-cell recognition during latency, as well as during lytic infection. We analyzed some of the molecular mechanisms that control MK3 expression. No dedicated MK3 mRNA was detected. Instead, the MK3 open reading frame (ORF) was transcribed as part of a bicistronic mRNA, downstream of a previously unidentified ORF, 13M. The 13M/MK3 promoter appeared to extend approximately 1 kb 5 of the transcription start site and included elements both dependent on and independent of the ORF50 lytic transactivator. MK3 was translated from the bicistronic transcript by virtue of an internal ribosome entry site (IRES) element. RNA structure mapping identified two stem-loops between 13M and MK3 that were sufficient for IRES activity in a bicistronic reporter plasmid and a third stem-loop just within the MK3 coding sequence, with a subtler, perhaps regulatory role. Overall, translation of the MHV-68 MK3 bore a striking resemblance to that of the Kaposi's sarcoma-associated herpesvirus vFLIP, suggesting that IRES elements are a common theme of latent gammaherpesvirus immune evasion in proliferating cells.The murine gammaherpesvirus 68 (MHV-68) is a natural parasite of mice (4, 5) that is related to the Kaposi's sarcomaassociated herpesvirus (KSHV). Thus, we can learn from MHV-68 something of how KSHV persists in immunocompetent hosts and causes disease. Some 90% of MHV-68 genes have clear position or sequence homologs in KSHV (42). However, the homology is greatest for the genes encoding structural virion components and essential lytic replication enzymes; there is much less conservation of host interaction genes such as those concerned with immune evasion. Of course, it is precisely these functions that are difficult to define in vitro and about which MHV-68 can be most informative. Thus, much of the utility of MHV-68 as a model for human disease mechanisms depends on identifying how the host interaction functions of each virus-assumed to have a greater commonality than is apparent from DNA sequence alignments-are distributed among their more variable genes.Immune evasion is a case in point. The list of immune evasion genes for either MHV-68 or KSHV genes is far from complete, but already the general impression is that those of each virus have evolved as a coordinated set, with the acquisition of a new gene leading to modified functions for the others. KSHV has two lytic cycle genes that downregulate major histocompatibility complex (MHC) class I expression, K3 and K5, while MHV-68 has just one, MK3 (10,17,37). An MHV-68 chemokine binding protein, M3, also mediates CD8 ϩ -T-cell evasion (7, 32) and may compensate for the lack of a K5, although exactly where it fits into in vivo pathogenesis remains controversial (41). M3 may also overlap in function with the KSHV vMIPs (26). In addition to its lytic cycle repertoire, KSHV has a late...

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A ?-herpesvirus immune evasion gene allows tumor cellsin vivo to escape attack by cytotoxic T cells specific for a tumor epitope

Cited by 23 publications

References 24 publications

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

CD4⁺ T cells specific for a model latency‐associated antigen fail to control a gammaherpesvirus in vivo

An InternalRibosome Entry Site Directs Translation of the Murine Gammaherpesvirus68 MK3 Open ReadingFrame

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A ?-herpesvirus immune evasion gene allows tumor cellsin vivo to escape attack by cytotoxic T cells specific for a tumor epitope

Cited by 23 publications

References 24 publications

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

An Ectromelia Virus Protein That Interacts with Chemokines through Their Glycosaminoglycan Binding Domain

CD4+ T cells specific for a model latency‐associated antigen fail to control a gammaherpesvirus in vivo

An InternalRibosome Entry Site Directs Translation of the Murine Gammaherpesvirus68 MK3 Open ReadingFrame

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CD4⁺ T cells specific for a model latency‐associated antigen fail to control a gammaherpesvirus in vivo