RESUMEN
The major obstacle to human immunodeficiency type 1 virus (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4+ T cells with high self-renewal capacity, such as central memory (CM) T cells and stem cell memory (SCM) T cells, are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/ß-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T cells, and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4+ T cells in the rhesus macaque (RM) model of simian immunodeficiency (SIV) infection. We used an inhibitor of the Wnt/ß-catenin pathway, PRI-724, that blocks the interaction between the coactivator CREB-binding protein (CBP) and ß-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIVmac251-infected RMs resulted in decreased proliferation of SCM and CM T cells and modified the SCM and CM CD4+ T cell transcriptome toward a profile of more differentiated memory T cells. However, short-term treatment with PRI-724 alone did not significantly reduce the size of the viral reservoir. This work demonstrates for the first time that stemness pathways of long-lived memory CD4+ T cells can be pharmacologically modulated in vivo, thus establishing a novel strategy to target HIV persistence.IMPORTANCE Long-lasting CD4+ T cell subsets, such as central memory and stem cell memory CD4+ T cells, represent critical reservoirs for human immunodeficiency virus (HIV) persistence despite suppressive antiretroviral therapy. These cells possess stem cell-like properties of enhanced self-renewal/proliferation, and proliferation of latently infected memory CD4+ T cells plays a key role in maintaining the reservoir over time. Here, we evaluated an innovative strategy targeting the proliferation of long-lived memory CD4+ T cells to reduce viral reservoir stability. Using the rhesus macaque model, we tested a pharmacological inhibitor of the Wnt/ß-catenin signaling pathway that regulates T cell proliferation. Our study shows that administration of the inhibitor PRI-724 decreased the proliferation of SCM and CM CD4+ T cells and promoted a transcriptome enriched in differentiation genes. Although the viral reservoir size was not significantly reduced by PRI-724 treatment alone, we demonstrate the potential to pharmacologically modulate the proliferation of memory CD4+ T cells as a strategy to limit HIV persistence.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Pirimidinonas/farmacología , Transducción de Señal/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Animales , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Proteína de Unión a CREB/antagonistas & inhibidores , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/inmunología , Diferenciación Celular/efectos de los fármacos , ADN Viral/antagonistas & inhibidores , ADN Viral/genética , ADN Viral/inmunología , Emtricitabina/farmacología , Femenino , Regulación de la Expresión Génica , Compuestos Heterocíclicos con 3 Anillos/farmacología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica/genética , Macaca mulatta , Masculino , Oxazinas , Piperazinas , Piridonas , Transducción de Señal/genética , Transducción de Señal/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Células Madre/efectos de los fármacos , Células Madre/inmunología , Células Madre/virología , Tenofovir/farmacología , Carga Viral/efectos de los fármacos , Latencia del Virus , Replicación Viral/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , beta Catenina/genética , beta Catenina/inmunologíaRESUMEN
The kanchanamycins, a group of novel 36-membered polyol macrolide antibiotics were detected in the culture filtrate and mycelium of Streptomyces olivaceus Tü 4018 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compounds show antibacterial and antifungal activities, and are especially effective against Pseudomonas fluorescens. Besides the kanchanamycin complex, strain Tü 4018 produces the 42-membered macrolactones, oasomycin A and desertomycin A, as well as tryptophan-dehydrobutyrine diketopiperazine and daidzein.