Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection

Turner, Damian; Cauley, Linda S.; Khanna, Kamal M.; Lefrançois, Leo

doi:10.1128/jvi.02167-06

Cited by 95 publications

(91 citation statements)

References 56 publications

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“…A critical question for measles is the causal relationship between persistence of MeV RNA and the induction of prolonged immune suppression and lifelong immunity. Considering that low levels of viral antigen are important for continued stimulation of CD8 + T cells after acute infections with influenza and vesicular stomatitis viruses (44,45), and that MeV RNA persists in the blood and lymphoid tissue for more than 2 mo after infection, we speculate that lifelong protective immunity after primary MeV infection could be a consequence of prolonged antigen stimulation. Because we predict that recrudescence of infectious MeV might occur in individuals with impaired humoral immune responses, another key area for future work is to assess implications for measles transmission and persistence at the population level.…”

Section: Resultsmentioning

confidence: 99%

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Lin

Kouyos

Adams

et al. 2012

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

109

136

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Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence is characteristic of primary infection. We found that viral RNA persisted in the blood, respiratory tract, or lymph nodes four to five times longer than the infectious virus and that the clearance of MeV RNA from blood happened in three phases: rapid decline coincident with clearance of infectious virus, a rebound phase with increases up to 10-fold, and a phase of slow decrease to undetectable levels. To examine the effect of individual host immune factors on MeV load dynamics further, we developed a mathematical model that expressed viral replication and elimination in terms of the strength of MeV-specific T-cell responses, antibody responses, target cell limitations, and immunosuppressive activity of regulatory T cells. Based on the model, we demonstrate that viral dynamics, although initially regulated by T cells, require antibody to eliminate viral RNA. These results have profound consequences for our view of acute viral infections, the development of prolonged immunity, and, potentially, viral evolution.immune responses | within-host modeling | virus clearance

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Section: Resultsmentioning

confidence: 99%

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Lin

Kouyos

Adams

et al. 2012

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

109

136

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“…Early experiments indicated that pMHCI complexes survive in only the very short term after infectious influenza A virus clearance (6,22), leading to the conclusion that the maintenance of influenza-specific CD8 ϩ T cell memory is antigen independent. Recent findings have suggested that influenza pMHCI complexes may persist for 1 month or more after the active infection is controlled (8,9,11,23). If this is indeed the case, it is incumbent on us to reinterpret the nature of influenza A virusspecific CD8 ϩ T cell memory.…”

Section: Discussionmentioning

confidence: 99%

Transience of MHC Class I-restricted antigen presentation after influenza A virus infection

Mintern

Bedoui²,

Davey³

et al. 2009

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

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Antigen expressed as MHC Class I glycoprotein (pMHCI) complexes on dendritic cells is the primary driver of CD8 ؉ T cell clonal expansion and differentiation. As we seek to define the molecular differences between acutely stimulated cytotoxic T lymphocyte (CTL) effectors and long-lived memory T cells, it is essential that we understand the duration of in vivo pMHCI persistence. Although infectious influenza A virus is readily cleared by mammalian hosts, that does not necessarily mean that all influenza antigen is totally eliminated. An exhaustive series of carefully controlled adoptive transfer experiments using 3 different carboxy fluorescein diacetate succinimidyl esterlabeled T cell receptor-transgenic CTL populations and a spectrum of genetically engineered and wild-type influenza A viruses provided no evidence for pMHCI persistence over the 30 -60-d interval after virus challenge. Molecular profiles identified in antigen-specific T cells at this time may thus be considered to reflect established immunologic memory and not recent CTL activation from a persistent pMHCI pool. V irus-specific CD8ϩ T cell-mediated immunity is a critical component of the host response. Naive CD8 ϩ T cells recognize virus-derived peptides presented in the context of MHC Class I glycoproteins (pMHCI). Encountering these pMHCI complexes on professional antigen-presenting cells (APCs) in draining lymph nodes (1) triggers CD8 ϩ T cell proliferation and differentiation (2, 3) to mediate cytotoxic T lymphocyte (CTL) effector function, a primary mechanism of virus clearance (4). Other clonally expanded CD8 ϩ T cells survive to establish a stable memory pool (2). Although it is possible to probe the molecular events that underlie these events using in vitro culture systems, what happens to T cells during and after an infectious challenge is optimally determined by minimizing the extent of manipulation after lymphocyte separation from the intact host. For example, we have recently demonstrated that a minority of influenza-specific memory CTLs recovered directly ex vivo can maintain cytotoxic gene expression for up to 1 year after infection (5). Understanding what this means in a molecular sense requires a clear picture of the likely stimulatory environment. Defining the importance of antigen load through the establishment and maintenance phases of CD8ϩ T cell immunity is also essential if we are to take rational approaches to vaccine design.Some viruses that first establish an acute, lytic infectious process have evolved mechanisms that allow them to persist at a low level (or in a latent form) for the life of the host. This is not the case for influenza in immunologically competent mice or, so far as we are aware, in other mammalian species. Numerous lines of evidence based on (i) feeding the thymidine analogue bromodeoxyuridine to monitor antigen-specific T cell expansion (6), (ii) isolating dendritic cells (DCs) to probe for pMHCI expression (7), and (iii) PCR to detect viral genome in the recovered lung (8-10) support the view that the...

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“…ns, P Ͼ 0.05; *, P Յ 0.05; **, P Յ 0.01; ***, P Յ 0.001 (by paired, two-tailed Student's t test). (51)(52)(53). Thus, we cannot rule out the possibility that residual lytic antigen or reactivation-associated antigen that is not suppressed by cidofovir treatment in vivo continuously interferes with restoration of CD8 ϩ T cell effector capabilities during MHV68 infection in IFNAR1 Ϫ/Ϫ mice.…”

Section: Ifnar1mentioning

confidence: 99%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

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CD8؉ T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8؉ T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1 ؊/؊ mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8 ؉ T cell response. To test this, IFNAR1 ؊/؊ mice were infected with MHV68 and the CD8 ؉ T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8 ؉ T cells, and MHV68-specific CD8 ؉ T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-␣), gamma IFN (IFN-␥), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8 ؉ T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1؊/؊ mice failed to improve CD8 ؉ T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8 ؉ T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8 ؉ T cell response. IMPORTANCE The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8 T he gammaherpesvirus-directed CD8ϩ T cell response is critical to the control of replication and reactivation associated with Epstein-Barr virus (EBV) infection, and individuals with either genetic or acquired immunodeficiencies are highly susceptible to EBV-associated diseases (1-3). Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4, 5). In addition, CD8 ϩ T cells prevent in vivo tumor outgrowth of B cell cancer lines immortalized by murine gammaherpesvirus 68 (MHV68), a wellcharacterized virus model for EBV (6). Thus, CD8ϩ T cells can suppress gammaherpesvirus-associated malignancies. The promise of immunotherapy and vaccine development relies on our understanding of factors that promote a highly effective gammaherpesvirus-directed CD8 ϩ T cell response. CD8 ϩ T cells responding to their cognate antigen require three signals for survival and differentiation: antige...

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Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection

Cited by 95 publications

References 56 publications

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Transience of MHC Class I-restricted antigen presentation after influenza A virus infection

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

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Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection

Cited by 95 publications

References 56 publications

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics

Transience of MHC Class I-restricted antigen presentation after influenza A virus infection

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Contact Info

Product

Resources

About

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection