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1.
Proc Natl Acad Sci U S A ; 117(51): 32566-32573, 2020 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-33288704

RESUMEN

Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4+ T cells. Trafficking of α4ß7-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of α4ß7 that is expressed on gut endothelial cells. MAdCAM signaling through α4ß7 costimulates CD4+ T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to α4ß7 In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through α4ß7 resulting in CD4+ T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-α4ß7 monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through α4ß7 likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/metabolismo , Integrinas/metabolismo , Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/farmacología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Epítopos/inmunología , Epítopos/metabolismo , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Interacciones Huésped-Patógeno/fisiología , Humanos , Activación de Linfocitos , Dominios Proteicos , Transducción de Señal , Virus de la Inmunodeficiencia de los Simios/inmunología , Tretinoina/farmacología
2.
Mucosal Immunol ; 11(5): 1342-1351, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29875402

RESUMEN

Human gut-associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues, however, is not fully understood. Access and migration of naive and memory CD4+ T cells to these sites is mediated by interactions between integrin α4ß7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with α4ß7. Such costimulation promotes high levels of HIV replication. An anti-α4ß7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4ß7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the upregulation of CCR5, while naive CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4ß7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4ß7 mAb, an analog of the clinically approved therapeutic vedolizumab, highlights the potential of such agents to control acute HIV infection.


Asunto(s)
Infecciones por VIH/metabolismo , VIH/fisiología , Integrinas/metabolismo , Replicación Viral/fisiología , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/virología , Femenino , VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Humanos , Memoria Inmunológica/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/virología , Tejido Linfoide/metabolismo , Tejido Linfoide/virología , Macaca mulatta , Dominios y Motivos de Interacción de Proteínas , Receptores CCR5/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tretinoina/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Replicación Viral/efectos de los fármacos
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