High Levels of Viremia in Patients with the Hantavirus Pulmonary Syndrome

Terajima, Masanori; Hendershot, John D.; Kariwa, Hiroaki; Koster, Frederick; Hjelle, Brian; Goade, Diane; DeFronzo, Matthew C.; Ennis, Francis A.

doi:10.1086/315153

Cited by 101 publications

(82 citation statements)

References 13 publications

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“…During HPS and DHF, very high levels of viremia are seen, and higher peak viral titers correlate with increased disease severity in both diseases (30,37). We speculate that virusspecific T cells are likely to contribute to the capillary leak syndromes observed in HPS and DHF (20,38,39).…”

Section: Virus-specific Cd8mentioning

confidence: 85%

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Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome

Kilpatrick¹,

Terajima²,

Koster

et al. 2004

The Journal of Immunology

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154

174

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We report on the role of specific CD8+ T cells in the pathogenesis of a highly lethal human viral disease, hantavirus pulmonary syndrome (HPS). HPS is a zoonotic disease caused by transmission of Sin Nombre virus (SNV) from chronically infected deer mice. In humans, this fulminant infection is characterized by lung capillary leakage, respiratory failure, and cardiogenic shock. Individuals with HLA-B*3501 have an increased risk of developing severe HPS, suggesting that CD8+ T cell responses to SNV contribute to pathogenesis. We identified three CD8+ T cell epitopes in SNV presented by HLA-B*3501 and quantitated circulating SNV-specific CD8+ T cells in 11 acute HPS patients using HLA/peptide tetramers. We found significantly higher frequencies of SNV-specific T cells in patients with severe HPS requiring mechanical ventilation (up to 44.2% of CD8+ T cells) than in moderately ill HPS patients hospitalized but not requiring mechanical ventilation (up to 9.8% of CD8+ T cells). These results imply that virus-specific CD8+ T cells contribute to HPS disease outcome. Intense CD8+ T cell responses to SNV may be induced by the encounter of the unnatural human host to this zoonotic virus without coevolution. This may also be the immunopathologic basis of other life-threatening human virus infections.

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Section: Virus-specific Cd8mentioning

confidence: 85%

“…Higher levels of viremia have been found in patients with severe HPS (30). Certain HLA alleles may be associated with highly efficient SNV Ag presentation, as has been speculated in HIV progression (41).…”

Section: Virus-specific Cd8mentioning

confidence: 93%

Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome

Kilpatrick¹,

Terajima²,

Koster

et al. 2004

The Journal of Immunology

Self Cite

154

174

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“…The fact that each hantavirus is associated with a singular primary host suggests that differences in virally regulated host proteins could limit the success of hantaviruses to selected mammals (6). In contrast to animals, transmission of hantaviruses to humans results in two diseases as well as viral clearance from patients and the failure of viruses to establish persistence (33,65,67). This suggests that tactics for cell regulation which are successful in small mammals fail in humans and instead may contribute to pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Residues Direct the Ubiquitination and Degradation of the NY-1 Hantavirus G1 Cytoplasmic Tail

Geimonen¹,

Fernandez²,

Gavrilovskaya³

et al. 2003

J Virol

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The hantavirus G1 protein contains a long C-terminal cytoplasmic tail of 142 residues. Hantavirus pulmonary syndrome-associated hantaviruses contain conserved tyrosine residues near the C terminus of G1 which form an immunoreceptor tyrosine activation motif (ITAM) and interact with Src and Syk family kinases. During studies of the G1 ITAM we observed that fusion proteins containing the G1 cytoplasmic tail were poorly expressed. Expression of G1 cytoplasmic tail constructs were dramatically enhanced by treating cells with the proteasome inhibitor ALLN, suggesting that the protein is ubiquitinated and degraded via the 26S proteasome. By using a 6-His-tagged ubiquitin, we demonstrated that the G1 cytoplasmic tail is polyubiquitinated and degraded in the absence of proteasome inhibitors. Expression of only the ITAM-containing domain also directed protein ubiquitination and degradation in the absence of upstream residues. Deleting the C-terminal 51 residues of G1, including the ITAM, stabilized G1 and blocked polyubiquitination and degradation of the protein. Site-directed mutagenesis of both ITAM tyrosines (Y619 and Y632) to phenylalanine also blocked polyubiquitination of G1 proteins and dramatically enhanced G1 protein stability. In contrast, the presence of Y627, which is not part of the ITAM motif, had no effect on G1 stability. Mutagenesis of just Y619 enhanced G1 stability, inhibited G1 ubiquitination, and increased the half-life of G1 by threefold. Mutating only Y632 had less of an effect on G1 protein stability, although Y619 and Y632 synergistically contributed to G1 instability. These findings suggest that Y619, which is conserved in all hantaviruses, is the primary signal for directing G1 ubiquitination and degradation. Collectively these findings indicate that specific conserved tyrosines within the G1 cytoplasmic tail direct the polyubiquitination and degradation of expressed G1 proteins and provide a potential means for down-regulating hantavirus G1 surface glycoproteins and cellular proteins that interact with G1.

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“…In HCPS, immunohistochemical studies of lung tissue showed the extensive distribution of viral antigens in endothelial cells, without evidence of cell necrosis. The viral antigens are also present at other sites, such as heart and lymphoid tissue (29). In the lungs, there is considerable infiltration of CD8 lymphocytes, which are also present in peripheral blood in the form of atypical lymphocytes.…”

Section: Pathogenymentioning

confidence: 99%

“…This test usually identifies the viral RNA within seven to ten days of disease onset. Sometimes there are significant differences among viruses isolated from different regions or countries, thus decreasing the technique sensitivity and hindering its use (15,22,29).…”

Section: Diagnosismentioning

confidence: 99%

Hantaviruses as emergent zoonoses

Ullmann¹,

Souza²,

Langoni³

2008

J. Venom. Anim. Toxins incl. Trop. Dis

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ABSTRACT:Hantaviruses belong to the Bunyaviridae family, which consists of vector-borne viruses. These viruses can provoke two infection types: hemorrhagic fever with renal syndrome (HFRS) -which occurs in the Old World -and hantavirus cardiopulmonary syndrome (HCPS) -an emergent zoonosis that can be found in many countries of the western hemisphere. Rodents are hantavirus reservoirs and each species seems to host a different virus type. Humans acquire the infection by inhaling contaminated aerosol particles eliminated by infected animals. The factors involved in the emergence of hantavirus infections in the human population include ecological modifications and changes in human activities. The most important risk factor is contact between man and rodents, as a result of agricultural, forestry or military activities. Rodent control remains the primary strategy for preventing hantavirus diseases, including via health education and hygienic habits.

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High Levels of Viremia in Patients with the Hantavirus Pulmonary Syndrome

Cited by 101 publications

References 13 publications

Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome

Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome

Tyrosine Residues Direct the Ubiquitination and Degradation of the NY-1 Hantavirus G1 Cytoplasmic Tail

Hantaviruses as emergent zoonoses

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