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1.
Virology ; 399(1): 1-10, 2010 Mar 30.
Article in English | MEDLINE | ID: mdl-20097400

ABSTRACT

Alphaviruses are mosquito-borne viruses that cause serious human and animal diseases. Previous studies demonstrated that a determinant within the nsP1/nsP2 cleavage domain of the virulent Sindbis AR86 virus played a key role in regulating adult mouse virulence without adversely affecting viral replication. Additional characterization of this determinant demonstrated that a virus with the attenuating mutation induced more type I IFN production both in vivo and in vitro. Interestingly, this phenotype was not specific to the Sindbis AR86 virus, as a similar mutation in a distantly related alphavirus, Ross River Virus (RRV), also led to enhanced IFN induction. This effect was independent of virus-induced host shutoff, since IRF-3 phosphorylation, which occurs independently of de novo host transcription/translation, was induced more robustly in cells infected with the mutant viruses. Altogether, these results demonstrate that critical determinants within the nsP1/nsP2 cleavage domain play an important role in regulating alphavirus-induced IFN responses.


Subject(s)
Interferon Type I/biosynthesis , Ross River virus/pathogenicity , Sindbis Virus/pathogenicity , Viral Nonstructural Proteins/physiology , Virulence Factors/physiology , Alphavirus Infections/metabolism , Alphavirus Infections/virology , Animals , Cell Line , Humans , Interferon Regulatory Factor-3/metabolism , L Cells , Mice , Mutagenesis, Site-Directed , Phosphorylation , Protein Biosynthesis/physiology , RNA/biosynthesis , Ross River virus/genetics , Ross River virus/physiology , Sindbis Virus/genetics , Sindbis Virus/physiology , Transcriptional Activation , Viral Nonstructural Proteins/genetics , Virulence Factors/metabolism
2.
Nat Immunol ; 9(3): 301-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18264102

ABSTRACT

Infection with human immunodeficiency virus 1 (HIV-1) results in the dissemination of virus to gut-associated lymphoid tissue. Subsequently, HIV-1 mediates massive depletion of gut CD4+ T cells, which contributes to HIV-1-induced immune dysfunction. The migration of lymphocytes to gut-associated lymphoid tissue is mediated by integrin alpha4beta7. We demonstrate here that the HIV-1 envelope protein gp120 bound to an activated form of alpha4beta7. This interaction was mediated by a tripeptide in the V2 loop of gp120, a peptide motif that mimics structures presented by the natural ligands of alpha4beta7. On CD4+ T cells, engagement of alpha4beta7 by gp120 resulted in rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Envelope Protein gp120/metabolism , HIV Infections/immunology , HIV-1/immunology , Integrins/metabolism , Intestinal Mucosa/immunology , CD4-Positive T-Lymphocytes/virology , Cell Movement/immunology , Cells, Cultured , Fibroblasts/metabolism , Fibroblasts/virology , Flow Cytometry , Humans , Intestinal Mucosa/virology , Killer Cells, Natural/immunology , Ligands , Lymphocyte Function-Associated Antigen-1/metabolism , Protein Binding/immunology , Signal Transduction/immunology
3.
Proc Natl Acad Sci U S A ; 103(10): 3746-51, 2006 Mar 07.
Article in English | MEDLINE | ID: mdl-16505369

ABSTRACT

HIV envelope binds to and signals through its primary cellular receptor, CD4, and through a coreceptor, either CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4). Here, we evaluate the response of peripheral blood mononuclear cells to a panel of genetically diverse R5 and X4 envelope proteins. Modulation of gene expression was evaluated by using oligonucleotide microarrays. Activation of transcription factors was evaluated by using an array of oligonucleotides encoding transcription factor binding sites. Responses were strongly influenced by coreceptor specificity. Treatment of cells from CCR5delta32 homozygous donors with glycoprotein (gp)120 derived from an R5 virus demonstrated that the majority of responses elicited by R5 envelopes required engagement of CCR5. R5 envelopes, to a greater extent than X4 envelopes, induced the expression of genes belonging to mitogen-activated protein kinase signal transduction pathways and genes regulating the cell cycle. A number of genes induced by R5, but not X4, envelopes were also up-regulated in the resting CD4+ T cell population of HIV-infected individuals. These results suggest that R5 envelope facilitates replication of HIV in the pool of resting CD4+ T cells. Additionally, signaling by R5 gp120 may facilitate the transmission of R5 viruses by inducing a permissive environment for HIV replication.


Subject(s)
HIV Envelope Protein gp120/immunology , HIV-1/immunology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , Cell Cycle/genetics , Cell Proliferation , Gene Expression Profiling , HIV Infections/genetics , HIV Infections/immunology , HIV Infections/pathology , HIV Infections/virology , HIV-1/pathogenicity , HIV-1/physiology , Humans , In Vitro Techniques , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Receptors, CCR5/metabolism , Receptors, CXCR4/metabolism , Signal Transduction , Transcription Factors/genetics , Virus Replication
4.
Virology ; 332(2): 491-7, 2005 Feb 20.
Article in English | MEDLINE | ID: mdl-15680414

ABSTRACT

Natural killer (NK) cells play an important role in both innate and adaptive antiviral immune responses. The adaptive response typically requires that virus-specific antibodies decorate infected cells which then direct NK cell lysis through a CD16 mediated process termed antibody-dependent cellular cytotoxicity (ADCC). In this report, we employ a highly polymerized chimeric IgG1/IgA immunoglobulin (Ig) fusion protein that, by virtue of its capacity to extensively crosslink CD16, activates NK cells while directing the lysis of infected target cells. We employ HIV as a model system, and demonstrate that freshly isolated NK cells preloaded with an HIV gp120-specific chimeric IgG1/IgA fusion protein efficiently lyse HIV-infected target cells at picomolar concentrations. NK cells pre-armed in this manner retain the capacity to kill targets over an extended period of time. This strategy may have application to other disease states including various viral infections and cancers.


Subject(s)
HIV Infections/immunology , Killer Cells, Natural/immunology , Antibody-Dependent Cell Cytotoxicity , Antigens, CD/immunology , Calcium Signaling/physiology , Cell Line, Tumor , Flow Cytometry , Humans , Immunoglobulin G/immunology , Immunotherapy/methods , Receptors, IgG/immunology
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