Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression

Bergthaler, Andréas; Flatz, Lukas; Hegazy, Ahmed N.; Johnson, Susan C.; Horvath, Edit; Löhning, Max; Pinschewer, Daniel D.

doi:10.1073/pnas.1011998107

Cited by 86 publications

(139 citation statements)

References 57 publications

(72 reference statements)

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“…Collectively, our data suggest that both the N37A and R55A mutant viruses are attenuated in vivo. It is worth mentioning that, for all mutant viral infections, animals that survived the infection did not contain any trace of infectious virus in the serum while all moribund animals had high viremia as determined by plaque assay, correlating with the previous reports that arenavirus virulence is associated with high levels of viral replication in vivo (3,21,31).…”

Section: Effects Of Ssp Mutations On Viral Virulence In Vivosupporting

confidence: 67%

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Shao

et al. 2016

J Virol

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Arenaviruses can cause lethal hemorrhagic fevers in humans with few preventative and therapeutic measures. The arenaviral glycoprotein stable signal peptide (SSP) is unique among signal peptides in that it is an integral component of the mature glycoprotein complex (GPC) and plays important roles not only in GPC expression and processing but also in the membrane fusion process during viral entry. Using the Pichinde virus (PICV) reverse genetics system, we analyzed the effects of alanine substitutions at many conserved residues within the SSP on viral replication in cell culture and in a guinea pig infection model. Our data showed that the K33A, F49A, and C57A mutations abolished GPC-mediated cell entry and therefore could not allow for the generation of viable recombinant viruses, demonstrating that these residues are essential for the PICV life cycle. The G2A mutation caused a marked reduction of cell entry at the membrane fusion step, and while this mutant virus was viable, it was significantly attenuated in vitro and in vivo. The N20A mutation also reduced membrane fusion activity and viral virulence in guinea pigs, but it did not significantly affect cell entry or viral growth in cell culture. Two other mutations (N37A and R55A) did not affect membrane fusion or viral growth in vitro but significantly reduced viral virulence in vivo. Taken together, our data suggest that the GPC SSP plays an essential role in mediating viral entry and also contributes to viral virulence in vivo. IMPORTANCESeveral arenaviruses, such as Lassa fever virus, can cause severe and lethal hemorrhagic fever diseases with high mortality and morbidity, and no FDA-approved vaccines or therapies are currently available. Viral entry into cells is mediated by arenavirus GPC that consists of an SSP, the receptor-binding GP1, and transmembrane GP2 protein subunits. Using a reverse genetics system of a prototypic arenavirus, Pichinde virus (PICV), we have shown for the first time in the context of virus infections of cell culture and of guinea pigs that the SSP plays an essential role in mediating the membrane fusion step as well as in other yet-to-be-determined processes during viral infection. Our study provides important insights into the biological roles of GPC SSP and implicates it as a good target for the development of antivirals against deadly human arenavirus pathogens.A renaviruses can cause neurologic or hemorrhagic fever diseases in humans, and few preventive or therapeutic measures are available (1, 2). The most significant arenavirus pathogen is Lassa fever virus (LASV), which causes infections that are endemic to many countries in West Africa, with an estimated 500,000 cases resulting in ϳ5,000 deaths annually (3). Except for Junin virus (JUNV), which has a vaccine, Candid#1, used only in Argentina, no licensed vaccine for human use is currently available for any other arenaviruses. Therapeutic options are limited and depend mainly on supportive care. Ribavirin, a nonspecific antiviral compound, has shown some efficacy ...

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Section: Effects Of Ssp Mutations On Viral Virulence In Vivosupporting

confidence: 67%

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Shao

et al. 2016

J Virol

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“…Compared with ARM, Cl13 exhibits >100-fold higher affinity for α-DG, more efficiently infects dendritic cells (DCs) and macrophages, replicates at a faster rate in these cells, and reaches higher viremia in mice (11)(12)(13)(14)(15). Accordingly, i.v.…”

Section: Resultsmentioning

confidence: 99%

“…ARM and Cl13 differ only at three amino acid positions: F260L and N176D in the glycoprotein GP1, and K1079Q in the L polymerase (POL). F260L in GP1 confers enhanced affinity of Cl13 to α-DG and facilitates virus binding and entry into DCs, the cell type that expresses >98% of α-DG located on immune cells (11,14,15,17,18); K1079Q in the L polymerase promotes enhanced (∼100-fold) Cl13 multiplication in DCs (15,18); conversely, N176D in GP1 does not play a significant role on the establishment of infection (14,15). To elucidate the role of these amino acid residues in the lethal disease caused by Cl13 in NZB mice, we used four recombinant LCMV (rLCMV) variants ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Baccalà¹,

Welch²,

Gonzalez-Quintial³

et al. 2014

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

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Significance Lassa virus is, after dengue virus, the second most common cause of viral hemorrhagic fever. In susceptible individuals, Lassa virus infection is associated with vascular permeability, leading to tissue edema, organ failure, and death. Hemorrhagic fever viruses efficiently infect vascular endothelial cells, but are generally considered noncytopathic. Thus, the mechanism of virus-induced vascular injury remains unclear. Using the lymphocytic choriomeningitis virus variant clone 13, a prototype of Lassa virus, we show here that lethal vascular leakage in susceptible mice was completely prevented by type I IFN receptor blockade. Therefore, approaches that target type I IFNs or effector molecules induced by these cytokines may be considered for the treatment of Lassa fever and other severe hemorrhagic viral illnesses.

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“…This is likely due to a high number of infected nonhematopoietic cells (with hepatocytes [36], fibroblastic reticular cells [33], lamina propria cells [37], glial cells and microglia being infected [38], and high expression of the LCMV receptor α-dystroglycan being present on stromal and epithelial cells [39] in many tissues, suggesting that these cells might also be infected) compared with hematopoietic cells (with mainly DCs [40,41] and macrophages [42] being infected by LCMV). However, by selective provision of antigen presentation in hematopoietic cells, CD8 + T-cell exhaustion can also be promoted, indicating that the overall amount of antigen, independent of the cell type (hematopoietic versus nonhematopoietic), can drive CD8 + T-cell exhaustion.The necessity of high antigen levels for the induction of CD8 + T-cell exhaustion was suggested in several settings of chronic infection such as LCMV infection of mice [25,43], repeated injection of antigen into mice [44], but also in humans a correlation between high antigen levels and T-cell exhaustion was observed after Mycobacterium tuberculosis [27] and HIV [24,26] infection. However, these studies were not able to distinguish whether increased exhaustion in the presence of more antigen is only due to the amount of antigen that is recognized by CD8 + T cells, or if certain cell types induce exhaustion more potently than others.…”

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confidence: 99%

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

2012

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Chronic viral infections lead to CD8 + T-cell exhaustion, characterized by impaired cytokine secretion and loss of proliferative capacity. While viral load and T-cell dysfunction correlate, it is currently unclear whether the quality of a cell type presenting antigen determines the degree of T-cell exhaustion or if the overall amount of antigen recognized by T cells promotes exhaustion. We found that chronic lymphocytic choriomeningitis virus infection led to decreased CD8 + T-cell exhaustion in DC-MHC class I (MHCI) mice, in which CD8 IntroductionDuring highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hierCorrespondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13]. Infection of mice with a low dose of the same virus strains results in an acute resolved infection [13].Besides a role for immunoregulatory cytokines such as 15], , a role for inhibitory receptor expression (reviewed in [18]) and perhaps regulatory T cells [19] C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2290-2304 HIGHLIGHTS 2291as well as the availability of T-cell help [10,20] and , the overall duration and amount of antigen exposure seems to be a critical parameter driving CD8 + T-cell exhaustion. Recent work has highlighted a negative correlation between viral load and CTL function in chronically infected humans and mice [24][25][26][27]. Even though these studies indicate that high overall antigen levels correlate with T-cell exhaustion, it was never directly shown whether alterations of antigen levels can substantially influence T-cell function independently of the cell type presenting the antigen in vivo. Furthermore, as T-cell exhaustion and viral persistence mutually depend on each other and since alterations in one of the parameters affects the other one, it is often difficult to assign causal relationships, particularly in humans.Here, we made use of Tg(CD11c-β2m) × Tg(K14-β2m) × β2m −/− (DC-MHCI, where DC is defined as dendritic cell; MHCI is defined as MHC class I) mice to assess the role of antigen presenting cells versus antigen load in induction of CD8 + T-cell exhaustion upon chronic LCMV infection. DC-MHCI mice are β2m −/− mice that transgenically express β2m in DCs, keratinocytes, and thymic cortical epithelial cells, ensuring positive selection of CD8 + T cells in the thymus [28]. Thus, DC-MHCI mice can mount normal endogenous CD8 + T-cell responses, but peripheral CD8 + T cells can o...

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Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression

Cited by 86 publications

References 57 publications

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

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Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression

Cited by 86 publications

References 57 publications

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

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Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell