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1.
PLoS Pathog ; 10(5): e1004123, 2014 May.
Article in English | MEDLINE | ID: mdl-24832205

ABSTRACT

Infections with monkeypox, cowpox and weaponized variola virus remain a threat to the increasingly unvaccinated human population, but little is known about their mechanisms of virulence and immune evasion. We now demonstrate that B22 proteins, encoded by the largest genes of these viruses, render human T cells unresponsive to stimulation of the T cell receptor by MHC-dependent antigen presentation or by MHC-independent stimulation. In contrast, stimuli that bypass TCR-signaling are not inhibited. In a non-human primate model of monkeypox, virus lacking the B22R homologue (MPXVΔ197) caused only mild disease with lower viremia and cutaneous pox lesions compared to wild type MPXV which caused high viremia, morbidity and mortality. Since MPXVΔ197-infected animals displayed accelerated T cell responses and less T cell dysregulation than MPXV US2003, we conclude that B22 family proteins cause viral virulence by suppressing T cell control of viral dissemination.


Subject(s)
Immune Evasion , Poxviridae Infections/immunology , Poxviridae/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/virology , Viral Proteins/physiology , Animals , CHO Cells , Cells, Cultured , Chlorocebus aethiops , Cricetinae , Cricetulus , Female , HEK293 Cells , Humans , Immune Evasion/genetics , Jurkat Cells , Macaca mulatta , Mice , Mice, Inbred BALB C , Mpox (monkeypox)/immunology , Poxviridae/genetics , Poxviridae/immunology
2.
J Virol ; 85(18): 9527-42, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21752919

ABSTRACT

Monkeypox virus (MPXV) is an orthopoxvirus closely related to variola virus, the causative agent of smallpox. Human MPXV infection results in a disease that is similar to smallpox and can also be fatal. Two clades of MPXV have been identified, with viruses of the central African clade displaying more pathogenic properties than those within the west African clade. The monkeypox inhibitor of complement enzymes (MOPICE), which is not expressed by viruses of the west African clade, has been hypothesized to be a main virulence factor responsible for increased pathogenic properties of central African strains of MPXV. To gain a better understanding of the role of MOPICE during MPXV-mediated disease, we compared the host adaptive immune response and disease severity following intrabronchial infection with MPXV-Zaire (n = 4), or a recombinant MPXV-Zaire (n = 4) lacking expression of MOPICE in rhesus macaques (RM). Data presented here demonstrate that infection of RM with MPXV leads to significant viral replication in the peripheral blood and lungs and results in the induction of a robust and sustained adaptive immune response against the virus. More importantly, we show that the loss of MOPICE expression results in enhanced viral replication in vivo, as well as a dampened adaptive immune response against MPXV. Taken together, these findings suggest that MOPICE modulates the anti-MPXV immune response and that this protein is not the sole virulence factor of the central African clade of MPXV.


Subject(s)
Monkeypox virus/immunology , Monkeypox virus/pathogenicity , Mpox (monkeypox)/immunology , Mpox (monkeypox)/pathology , Viral Proteins/metabolism , Virulence Factors/metabolism , Adaptive Immunity , Animals , B-Lymphocytes/immunology , Blood/virology , DNA, Viral/chemistry , DNA, Viral/genetics , Disease Models, Animal , Female , Gene Deletion , Lung/virology , Macaca mulatta , Male , Molecular Sequence Data , Mpox (monkeypox)/virology , Primate Diseases/immunology , Primate Diseases/pathology , Primate Diseases/virology , Sequence Analysis, DNA , Skin/pathology , T-Lymphocytes/immunology , Viral Proteins/genetics , Virulence Factors/genetics
3.
PLoS One ; 5(12): e15514, 2010 Dec 02.
Article in English | MEDLINE | ID: mdl-21151986

ABSTRACT

BACKGROUND: Risk of encephalitis from West Nile virus (WNV) infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old non-human primates. METHODOLOGY/PRINCIPAL FINDINGS: We investigated clinical, immunological and virological correlates of WNV infection in aging non-human primates. Aged (17-30 yrs) and adult (6-9 yrs) Rhesus macaques (RM) were challenged with WNV in the presence or the absence of the mosquito salivary gland extract (SGE) to approximate natural infection. None of the 26 animals exhibited clinical signs of the disease. Quantitative PCR suggested discrete and short-lived viremia, but infectious virus was never isolated. There was markedly increased, age-independent, proliferation of CD3(-) non-B cells, followed by B-cell proliferation, which correlated to the loss of detectable WNV genomes. Moreover, animals primed with mosquito salivary gland extract exhibited reduced circulating WNV RNA. While we found the expected age-associated reduction in T cell proliferation, adaptive immunity did not correlate with infection outcome. That was further confirmed in a cohort of thymectomized and/or CD8 T-cell depleted Cynomolgus macaques (CM; N = 15), who also failed to develop WNV disease. CONCLUSIONS/SIGNIFICANCE: Results are consistent with strong and age-independent innate resistance of macaques against WNV challenge. This animal model is therefore not suitable for vaccine and therapeutic testing against WNV. However, understanding the basis of their innate resistance against WNV in macaques could provide helpful clues to improve anti-WNV protection of older adults.


Subject(s)
Aging , West Nile Fever/immunology , West Nile Fever/virology , West Nile virus/metabolism , Animals , Culicidae , Disease Models, Animal , Female , Genome, Viral , Immune System , Leukocytes/virology , Macaca , Macaca fascicularis , Male , Primates , Salivary Glands/virology , Strigiformes
4.
Blood ; 112(10): 4227-34, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-18757778

ABSTRACT

Rhesus macaque rhadinovirus (RRV) is closely related to Kaposi sarcoma-associated herpesvirus (KSHV) and is associated with the development of B-cell hyperplasia and persistent lymphadenopathy resembling multicentric Castleman disease in rhesus macaques (RMs) coinfected with simian immunodeficiency virus (SIV). Here we investigated whether RMs experimentally infected with SIV and RRV can develop other disease manifestations observed in HIV- and KSHV-infected patients. As reported earlier, inoculation of SIV-infected RMs with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia 2 weeks after infection, followed by a period of no virus detection until they are subsequently made immunodeficient by SIV infection. A subset of animals developed abnormal cellular proliferations characterized as extranodal lymphoma and a proliferative mesenchymal lesion. In situ hybridization and immunohistochemistry analysis indicate RRV is present in both malignancies, and DNA microarray analysis detected viral interleukin-6 (vIL-6) and viral FLICE-like inhibitory protein (vFLIP) transcripts. Reverse-transcriptase polymerase chain reaction analysis confirmed vIL-6 and vFLIP expression, and that of RRV open reading frames 72 and 73, homologs of KSHV open reading frames shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV-/SIV-infected RM as an excellent animal model to investigate KSHV-like pathogenesis.


Subject(s)
Disease Models, Animal , HIV Infections/virology , HIV , Herpesviridae Infections/metabolism , Herpesvirus 8, Human/metabolism , Lymphoma, Non-Hodgkin/metabolism , Rhadinovirus/metabolism , Simian Acquired Immunodeficiency Syndrome/metabolism , Simian Immunodeficiency Virus , Tumor Virus Infections/metabolism , Animals , Castleman Disease/metabolism , Castleman Disease/virology , Gene Expression Regulation, Leukemic , Gene Expression Regulation, Viral , HIV Infections/metabolism , Herpesviridae Infections/virology , Humans , Lymphoma, Non-Hodgkin/virology , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/virology , Tumor Virus Infections/virology , Viral Proteins/biosynthesis
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