RESUMEN
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.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Integrinas/metabolismo , Mucosa Intestinal/inmunología , Linfocitos T CD4-Positivos/virología , Movimiento Celular/inmunología , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/virología , Citometría de Flujo , Humanos , Mucosa Intestinal/virología , Células Asesinas Naturales/inmunología , Ligandos , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Unión Proteica/inmunología , Transducción de Señal/inmunologíaRESUMEN
Both activated and resting CD4(+) T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin alpha(4)beta(7) (alpha(4)beta(7)), the gut mucosal homing receptor. We find that alpha(4)beta(7)(high) CD4(+) T cells are more susceptible to productive infection than are alpha(4)beta(7)(low-neg) CD4(+) T cells in part because this cellular subset is enriched with metabolically active CD4(+) T cells. alpha(4)beta(7)(high) CD4(+) T cells are CCR5(high) and CXCR4(low); on these cells, alpha(4)beta(7) appears in a complex with CD4. The specific affinity of gp120 for alpha(4)beta(7) provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.
Asunto(s)
Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Integrinas/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/virología , Anticuerpos Monoclonales/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Membrana Celular/efectos de los fármacos , Membrana Celular/inmunología , Membrana Celular/virología , Femenino , Genitales Femeninos/efectos de los fármacos , Genitales Femeninos/inmunología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Inmunoprecipitación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptores CCR5/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses against viral infections. pDCs secrete type I IFNs and proinflammatory cytokines upon stimulation by either TLR7 or TLR9. Throughout the course of HIV infection, the production of type-I IFNs is profoundly impaired, and total pDC cell counts in peripheral blood correlates inversely with viral load and positively with CD4(+) T cell count. The origin of these defects is unclear. pDCs express CD4, CCR5, and CXCR4, the primary receptor and coreceptors, respectively, for the HIV envelope; yet little is known concerning the effects of the viral envelope on these cells. Here, we show that exposure of pDCs to gp120 results in the suppression of activation of these cells. This suppression is specific for TLR9-mediated responses, because TLR7-mediated responses are unaffected by gp120. gp120 also suppressed TLR9-mediated induction of proinflammatory cytokines and expression of CD83, a marker of DC activation. Finally, gp120 suppressed pDC-induced cytolytic activity of natural killer cells. Taken together, these data demonstrate that the direct interaction of HIV-1 gp120 with pDCs interferes with TLR9 activation resulting in a decreased ability of pDCs to secrete antiviral and inflammatory factors that play a central role in initiating host immune responses against invading pathogens.