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1.
J Infect Dis ; 208(5): 830-8, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23757341

RESUMEN

BACKGROUND: Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1-infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1-induced interferon-alpha (IFN-α) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1-associated immune activation observed. METHODS: T-cell and dendritic cell populations were isolated from treatment-naive chronically HIV-1-infected individuals enrolled in the Adult Clinical Trials Group 384 by fluorescence-activated cell sorting. The expression of 98 genes involved in Toll-like receptor and type I IFN signaling pathways were quantified using Nanostring technology. RESULTS: Several ISGs were significantly correlated with HIV-1 viral load and/or CD4(+) T-cell count. Higher expression levels of a subset of these ISGs were observed in cells derived from females as compared to males after adjusting for viral load and were correlated to higher levels of T-cell activation. CONCLUSION: These data show that higher IFN-α production is associated with higher ex vivo expression of several ISGs in females. This might contribute to higher levels of immune activation and the observed faster HIV-1 disease progression in females for a given level of viral replication.


Asunto(s)
Regulación de la Expresión Génica , Infecciones por VIH/inmunología , VIH-1/inmunología , Interferón-alfa/inmunología , Linfocitos T/inmunología , Adulto , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad
2.
AIDS ; 26(5): 533-41, 2012 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-22210629

RESUMEN

OBJECTIVE AND DESIGN: The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. TLRs serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have come to varying conclusions. METHODS: Using intracellular flow cytometry, cytokine production by cryopreserved peripheral blood mononuclear cells from healthy controls and HIV-1-infected individuals were examined after TLR stimulation. RESULTS: We observed that the effect of HIV-1 infection on TLR responses not only depended on the stage of HIV-1 infection, but was also dependent on the individual receptor and cell type examined. Monocyte and myeloid dendritic cell responses to TLR8 stimulation were associated with HIV-1 viral load and CD4 T-cell count, whereas plasmacytoid dendritic cell responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection, whereas responses to TLR9 stimulation were universally decreased in all HIV-1-infected individuals examined regardless of treatment or clinical parameters. CONCLUSION: Responsiveness to TLR7/8 stimulation, which have been shown to recognize HIV-1 ssRNA, did not decrease in chronic infection, and may represent a contributing factor to ongoing T-cell immune activation in the setting of chronic viremic HIV-1 infection.


Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Receptores Toll-Like/inmunología , Enfermedad Aguda , Adulto , Anciano , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Enfermedad Crónica , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Infecciones por VIH/metabolismo , VIH-1/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/inmunología , Receptor Toll-Like 8/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Carga Viral , Adulto Joven
3.
AIDS ; 25(5): 715-7, 2011 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-21297422

RESUMEN

Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-α (IFN-α), and the ability of plasmacytoid dendritic cells to produce IFN-α in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression.


Asunto(s)
Células Dendríticas/metabolismo , VIH-1/genética , Factor 7 Regulador del Interferón/genética , Interferón-alfa/biosíntesis , Polimorfismo Genético/genética , Receptor Toll-Like 9/genética , Humanos , Transducción de Señal
4.
Nat Med ; 15(8): 955-9, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19597505

RESUMEN

Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8(+) T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1-associated pathology.


Asunto(s)
Células Dendríticas/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Caracteres Sexuales , Receptor Toll-Like 7/fisiología , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/metabolismo , VIH-1/fisiología , Humanos , Interferón-alfa/metabolismo , Activación de Linfocitos/inmunología , Masculino , Progesterona/sangre , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/metabolismo , Carga Viral
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