Evidence for a viral superantigen in humans

Lafon, Monique; Lafage, Mireille; Martínez-Arends, A.; Ramı́rez, Rafael; Vuillier, Françoise; Charron, Dominique; Lotteau, Vincent; Scott‐Algara, Daniel

doi:10.1038/358507a0

Cited by 169 publications

(73 citation statements)

References 27 publications

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“…The high efficacy of RV in inducing an antiviral immune response may also be due to the stimulation of immunocytes by RV components. Lafon and colleagues demonstrated that the nucleocapsid of RV acts as a viral superantigen, which activates T lymphocytes bearing particular V beta subsets of T cell receptor via its binding to major histocompatibility complex class II (2,47,48).…”

mentioning

confidence: 99%

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

Nakamichi¹,

Inoue

Takasaki³

et al. 2004

J Virol

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Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.Rabies virus (RV) is a negative-strand RNA virus belonging to the Rhabdoviridae family, genus Lyssavirus. Most RV strains are highly neurotropic, which usually causes a fatal infection in warm-blooded animals, and viral replication primarily occurs in neurons as a cellular target (43). It has been reported that RV replicates in muscle cells prior to the invasion of the peripheral nervous system and central nervous system (CNS) in vivo (62). In vitro, it is known that a highly neurovirulent RV strain, challenge virus standard (CVS), and an attenuated strain, high egg passage (HEP)-Flury (hereafter called HEP), infect a variety of cell types, including nonneuronal cells (26,82,84,85).It is well known that infection of experimental animals with nonpathogenic RV strains triggers a strong antiviral immune response (90). Recent studies have demonstrated that the strong antiviral immune response elicited by attenuated RV infection is closely related to the induction of apoptosis in infected cells due to the expression of viral glycoprotein (61,76). Several groups have attempted to develop vaccine vehicles using RV-based vectors. It has been reported that the RV vectors expressing foreign antigens induce strong humoral and cellular responses against other kinds of viral pathogens, s...

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mentioning

confidence: 99%

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

Nakamichi¹,

Inoue

Takasaki³

et al. 2004

J Virol

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“…Since the presentation of an MHC II-peptide complex by the B cell is unlikely [9,11], HIV-associated superantigens may contribute to T cell activation by TCR triggering [17,19,20]. However, if HIVassociated gp120 indeed acted as viral superantigen in B cell/T cell co-cultures, infection with non-opsonized virus should also lead to viral replication and p24 antigen production.…”

Section: Discussionmentioning

confidence: 99%

Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

et al. 2003

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Resting CD4 + T cells in the lymphoid tissue (LT) are essential producers of virions at the beginning of HIV infection in vivo. We previously developed a model that allowed in vitro infection of non-prestimulated T lymphocytes in the presence of autologous B lymphocytes and complement. In this study, we try to clarify the mechanism(s) responsible for virus transmission in unstimulated autologous B cell/T cell co-cultures. Ex vivo analyses of patient plasma samples revealed that HIV was opsonized. Flow cytometry showed that opsonized virus preferentially bound to complement receptor (CR)-2 on B lymphocytes in primary B cell/T cell co-cultures. As indicated by cytokine measurements and transwell experiments, soluble factors seemed to play a minor role in enabling infection. Rather, direct interaction between B and T lymphocytes and direct binding of opsonized virus to CR2 on B cells turned out to be essential for productive infection. Antibodies blocking cell-cell adhesion inhibited p24 antigen production. An anti-CR2 antibody blocking C3d-CR2 binding also significantly reduced viral replication. Since the infection of unstimulated T cells by opsonized primary HIV isolates in the presence of B cells was highly efficient independent of the tropism of the virus, this mechanism may be critical in the pathogenesis of HIV.

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“…The use of a recombinant chimeric RV͞VSV would have an advantage, compared with the use of recombinant HIV-1 gp120, to display the properly folded HIV-1 envelope protein on the surface of the infected cell. In addition, repeated expression of the RV nucleoprotein, which was previously shown to be an exogenous superantigen (37,38), might help to enhance the immune response against the HIV-1 envelope. The RV N protein is an excellent immunogen and was shown to enhance the immune response against feline immunodeficiency virus, when used in combination with the feline immunodeficiency virus surface glycoproteins (39).…”

Section: Discussionmentioning

confidence: 99%