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1.
PLoS One ; 14(1): e0211112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682108

RESUMO

Blockade of the programmed cell death protein/ligand 1 (PD-1/PD-L1) pathway with monoclonal antibodies (mAb) is now commonly used for cancer immunotherapy and has therapeutic potential in chronic viral infections including HIV-1. PD-1/PD-L1 blockade could augment HIV-1-specific immune responses and reverse HIV-1 latency, but the latter effect has not been clearly shown. We tested the ability of the human anti-PD-L1 mAb BMS-936559 and the human anti-PD-1 mAb nivolumab to increase HIV-1 virion production ex vivo from different peripheral blood mononuclear cell populations obtained from donors on suppressive antiretroviral therapy (ART). Fresh peripheral blood mononuclear cells (PBMC), CD8-depleted PBMC, total CD4+ T cells, and resting CD4+ T cells were purified from whole blood of HIV-1-infected donors and cultured in varying concentrations of BMS-936559 (20, 5, or 1.25µg/mL) or nivolumab (5 or 1.25µg/mL), with or without anti-CD3/CD28 stimulatory antibodies. Culture supernatants were assayed for virion HIV-1 RNA by qRT-PCR. Ex vivo exposure to BMS-936559 or nivolumab, with or without anti-CD3/CD28 stimulation, did not consistently increase HIV-1 virion production from blood mononuclear cell populations. Modest (2-fold) increases in virus production were observed in a subset of donors and in some cell types but were not reproducible in longitudinal samples. Cell surface expression of PD-1 and PD-L1 were not associated with changes in virus production. Ex vivo blockade of the PD-1 axis alone has limited effects on HIV-1 latency.


Assuntos
Antirretrovirais/farmacologia , Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Nivolumabe/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Vírion/metabolismo , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Anticorpos Monoclonais Humanizados , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Receptor de Morte Celular Programada 1/metabolismo
2.
PLoS One ; 5(9): e12926, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20886079

RESUMO

BACKGROUND: Programmed Death-1 (PD-1) is an inhibitory member of the CD28 family of molecules expressed on CD8+ T cells in response to antigenic stimulation. To better understand the role of PD-1 in antiviral immunity we examined the expression of PD-1 on Epstein-Barr virus (EBV) epitope-specific CD8+ T cells during acute infectious mononucleosis (AIM) and convalescence. METHODOLOGY/PRINCIPAL FINDINGS: Using flow cytometry, we observed higher frequencies of EBV-specific CD8+ T cells and higher intensity of PD-1 expression on EBV-specific CD8+ T cells during AIM than during convalescence. PD-1 expression during AIM directly correlated with viral load and with the subsequent degree of CD8+ T cell contraction in convalescence. Consistent differences in PD-1 expression were observed between CD8+ T cells with specificity for two different EBV lytic antigen epitopes. Similar differences were observed in the degree to which PD-1 was upregulated on these epitope-specific CD8+ T cells following peptide stimulation in vitro. EBV epitope-specific CD8+ T cell proliferative responses to peptide stimulation were diminished during AIM regardless of PD-1 expression and were unaffected by blocking PD-1 interactions with PD-L1. Significant variability in PD-1 expression was observed on EBV epitope-specific CD8+ T cell subsets defined by V-beta usage. CONCLUSIONS/SIGNIFICANCE: These observations suggest that PD-1 expression is not only dependent on the degree of antigen presentation, but also on undefined characteristics of the responding cell that segregate with epitope specificity and V-beta usage.


Assuntos
Antígenos CD/genética , Proteínas Reguladoras de Apoptose/genética , Linfócitos T CD8-Positivos/imunologia , Herpesvirus Humano 4/fisiologia , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Antígenos CD/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Expressão Gênica , Herpesvirus Humano 4/imunologia , Humanos , Mononucleose Infecciosa/virologia , Receptor de Morte Celular Programada 1 , Receptores de Antígenos de Linfócitos T/genética , Regulação para Cima
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