Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection.

BACKGROUND.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule-a novel Toll-like receptor 9 (TLR9) agonist, MGN1703-could function as an enhancer of innate immunity and an LRA in vivo. METHODS.: We conducted a single-arm, open-label study in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (NK), and T-cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration. RESULTS.: In accordance with the cell type-specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing, suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range, 21-1571 copies/mL) during treatment. CONCLUSIONS.: TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy. CLINICAL TRIALS REGISTRATION.: NCT02443935.

The thioacetate-ω(γ-lactam carboxamide) HDAC inhibitor ST7612AA1 as HIV-1 latency reactivation agent.

Antiretroviral therapy (ART) is unable to cure HIV infection. The ability of HIV to establish a subset of latent infected CD4(+) T cells, which remain undetectable to the immune system, becomes a major roadblock to achieve viral eradication. Histone deacetylase inhibitors (HDACi) have been shown to potently induce the reactivation of latent HIV. Here, we show that a new thiol-based HDACi, the thioacetate-ω(γ-lactam carboxamide) derivative ST7612AA1, is a potent inducer of HIV reactivation. We evaluated HIV reactivation activity of ST7612AA1 compared to panobinostat (PNB), romidepsin (RMD) and vorinostat (VOR) in cell culture models of HIV-1 latency, in latently infected primary CD4(+) T lymphocytes and in PBMCs from HIV(+) patients. ST7612AA1 potently induced HIV-1 reactivation at submicromolar concentrations with comparable potency to panobinostat or superior to vorinostat. The presence of known antiretrovirals did not affect ST7612AA1-induced reactivation and their activity was not affected by ST7612AA1. Cell proliferation and cell activation were not affected by ST7612AA1, or any other HDACi used. In conclusion, our results indicate that ST7612AA1 is a potent activator of latent HIV and that reactivation activity of ST7612AA1 is exerted without activation or proliferation of CD4(+) T cells. ST7612AA1 is a suitable candidate for further studies of HIV reactivation strategies and potential new therapies to eradicate the viral reservoirs.

Eficacia del tratamiento para la afasia de Wernicke en pacientes con sintomatología grave / Effective treatment for Wernicke's aphasia in patients with severe symptomatology

Introducción. La afasia es un trastorno del lenguaje que en la mayoría de los casos provoca una incapacidad para la comunicación, lo que implica un hándicap no solo para el paciente sino para el entorno familiar. La rehabilitación del paciente se considera, entonces, vital para suplir esta disfunción comunicativa. La terapia logopédica convencional es útil, pero en casos de afasias con graves alteraciones es lenta. Para subsanar este problema, en el ámbito de la afasia de Wernicke se desarrolló el «tratamiento para la afasia de Wernicke» (TAW), que se mostró efectivo en un conjunto específico de candidatos. Objetivo. Valorar el TAW en pacientes diagnosticados con afasia de Wernicke y que presentan una sintomatología grave, aunque no sean candidatos específicos al tratamiento original. Método. Se realizaron 12 sesiones del TAW con un paciente afectado por afasia de Wernicke y se comparó la actuación pre y postratamiento de este paciente con un grupo de pacientes con afasia de Wernicke (uno de ellos con igual etiología y localización) y otro grupo de pacientes con afasia sensorial transcortical (afasia de Wernicke tipo ii). Resultados. Los resultados muestran, en casi todos los ámbitos verbales analizados, una mejora mayor en el paciente que realizó el TAW respecto al resto de pacientes que siguieron una terapia logopédica convencional. Conclusiones. A partir de los resultados obtenidos se concluye que el TAW es un tratamiento terapéutico útil para toda clase de pacientes con afasia de Wernicke, y no solo para los candidatos propuestos en la rehabilitación inicial (AU)

Introduction. Aphasia is a language disorder which causes, in most cases, an inability to communicate, which implies a handicap not only for the patient but also for the family environment. Patient rehabilitation is considered vital to redress this communicative dysfunction. Conventional speech therapy is useful, but for cases of aphasia with severe disturbances it is too slow. To solve this problem, in the field of the Wernicke's aphasia was developed the Treatment for the Wernicke's aphasia (TWA), which it is showed effective in a specific set of candidates. Objective. To assess TWA in Wernicke's aphasia patients who had severe symptoms, although they were not candidates for the original conventional treatment. Method. 12 sessions of TWA were performed with a Wernicke's patient, and pre- and post-treatment results of the patient were compared with a group of Wernicke's patients (one with the same etiology and location) and with a group of transcortical sensory aphasia's patients (Wernicke aphasia type ii). Results. The results show, in almost all the analyzed verbal areas, a greater improvement in the patient who completed the TWA compared to patients who followed conventional speech therapy. Conclusions. From the results obtained in this study it can be concluded that the TWA is an useful therapeutic treatment for all classes of patients with Wernicke's aphasia, and not just for the candidates in initial rehabilitation (AU)