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ObjectivesSome drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or Simian Immunodeficiency Virus (SIV), but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses.DesignTo investigate this hypothesis, drugs were tested ex vivo on peripheral blood mononuclear cells (PBMC) from nine antiretroviral therapy (ART)-suppressed individuals.MethodsWe tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant [inhibitor of apoptosis proteins (IAP) inhibitor], bortezomib (proteasome inhibitor), and INK128/sapanisertib [mammalian target of rapamycin mTOR] [c]1/2 inhibitor). After 6 days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay).ResultsObatoclax reduced intact HIV DNA [median = 27-30% of dimethyl sulfoxide control (DMSO)] but not defective or total HIV DNA. Other drugs showed no statistically significant effects.ConclusionObatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

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Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum Presepsin, immunosuppressive acid protein (IAP), high mobility group B1 (HMGB1) and prognosis of percutaneous transhepatic cholangial drainage (PTCD) treatment in patients with acute obstructive suppurative cholangitis (AOSC). Methods: 220 patients with AOSC who received PTCD treatment in the Baoding Second Central Hospital from January 2021 to January 2023 were selected to be included in the AOSC group, and 88 healthy volunteers during the same period were selected to be included in the control group. The patients with AOSC were divided into survival group with 36 cases and death group with 184 cases according to whether they died during hospitalization after PTCD surgical. Serum Presepsin, IAP and HMGB1 levels were detected. Multivariate Logistic regression model was used to analyze the factors affecting the prognosis of PTCD surgical treatment in patients with AOSC, the predictive value of serum Presepsin, IAP and HMGB1 levels on postoperative death in patients with AOSC after PTCD surgical was analyzed by receiver operating characteristic (ROC) curve. Results: The serum Pressin, IAP, and HMGB1 levels in the AOSC group were higher than those in the control group (P＜0.05). The mortality rate during hospitalization after PTCD surgical in 220 patients with AOSC was 16.36% (36/220). Multivariate Logistic regression analysis showed that, time from onset to surgery ≥3 d, 24 h postoperative bile drainage ＜300 m L, elevated Presepsin, elevated IAP, and elevated HMGB1 were independent risk factors affecting the prognosis of PTCD treatment in patients with AOSC (P＜0.05). ROC curve analysis showed that, the area under the curve of serum Presepsin, IAP, and HMGB1 levels combined to predict postoperative death after PTCD surgical in patients with AOSC was 0.920, which was greater than the single indicator prediction. Conclusion: Elevated serum Presepsin, IAP, and HMGB1levels in patients with AOSC are independent risk factors for the prognosis of PTCD treatment. The combination of serum presepsin, IAP, and HMGB1 levels has high value in predicting the prognosis of PTCD treatment in patients with AOSC. [ABSTRACT FROM AUTHOR]

Copyright of Prospectiva is the property of Universidad del Valle and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

La condición de seropositividad implica un nuevo comienzo para las personas debido a que se presenta una escisión de su persona y requieren una reconstrucción de su vida. A nivel social, la deconstrucción vital puede estar caracterizada por la ausencia de poder y presencia de estigma social, lo que puede impactar en la afectividad y la participación comunitaria de las personas que viven con VIH (PVV). Este trabajo de sistematización tiene como objetivo reconstruir el proceso de una intervención llevada a cabo desde la Investigación Acción Participativa (IAP), para lo cual se retomó la Teoría de las Representaciones Sociales, con el fin de aproximarse a los componentes socioafectivos de un grupo de PVV y su relación con el estigma y la participación comunitaria. Se encontró que la afectividad representa un aspecto importante, siendo el diagnóstico un aspecto central en la modificación de sus significados y prácticas vitales, con tendencia hacia el aislamiento y baja participación social. Mediante la intervención, las personas participantes se fueron asumiendo como agentes de cambio, derivando un rompimiento con el estigma del VIH/SIDA, tanto intragrupal como con la comunidad. Se puede concluir que, construir procesos participativos desde la afectividad puede conducir al re-conocimiento y la potenciación de sus fortalezas.

ABSTRACT Latency reversal and subsequent elimination of the human immunodeficiency virus-1 (HIV-1) reservoir using a combination of compounds with different mechanisms of action are considered a promising tool for HIV-1 cure. Here, we analyzed HIV-1 reservoir reduction by targeting the two host factors; inhibitor of apoptosis proteins (IAPs) and DEAD-box polypeptide 3 (DDX3) using a SMAC mimetic (SMACm) and DDX3 inhibitor (DDX3i), respectively. We observed that SMACm efficiently reactivated HIV-1 in a latency Jurkat model, which was further enhanced by DDX3 inhibition. Strikingly, this compound combination strongly decreased the proportion of latently as well as transcriptionally active infected cells in a T cell line model with a dual-reporter virus. To determine the efficacy of compounds to eradicate the HIV-1 reservoir in people living with HIV (PWH), a novel ex vivo HIV-1 reservoir reduction assay (HIVRRA) was developed. DDX3i and SMACm alone reduced the HIV-1 reservoir in peripheral blood mononuclear cells (PBMCs) from the majority of PWH, whereas notably, the SMACm/DDX3i combination reduced the HIV-1 reservoir even further with 53%–90% in all PWH analyzed, while uninfected bystander cells were not affected. Our data highlight that IAPs as well as factors involved in HIV-1 replication like DDX3 are excellent targets for HIV-1 cure strategies. We show for the first time that the combination of SMACm and DDX3i reverses viral latency and specifically eliminates the HIV-1-infected cells in vitro and ex vivo. IMPORTANCE HIV-1 continues to be a major global health challenge. Current HIV-1 treatments are effective but need lifelong adherence. An HIV-1 cure should eliminate the latent viral reservoir that persists in people living with HIV-1. Different methods have been investigated that focus on reactivation and subsequent elimination of the HIV-1 reservoir, and it is becoming clear that a combination of compounds with different mechanisms of actions might be more effective. Here, we target two host factors, inhibitor of apoptosis proteins that control apoptosis and the DEAD-box helicase DDX3, facilitating HIV mRNA transport/translation. We show that targeting of these host factors with SMAC mimetics and DDX3 inhibitors induce reversal of viral latency and eliminate HIV-1-infected cells in vitro and ex vivo.

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Importance: HIV-1 continues to be a major global health challenge. Current HIV-1 treatments are effective but need lifelong adherence. An HIV-1 cure should eliminate the latent viral reservoir that persists in people living with HIV-1. Different methods have been investigated that focus on reactivation and subsequent elimination of the HIV-1 reservoir, and it is becoming clear that a combination of compounds with different mechanisms of actions might be more effective. Here, we target two host factors, inhibitor of apoptosis proteins that control apoptosis and the DEAD-box helicase DDX3, facilitating HIV mRNA transport/translation. We show that targeting of these host factors with SMAC mimetics and DDX3 inhibitors induce reversal of viral latency and eliminate HIV-1-infected cells in vitro and ex vivo ., Competing Interests: M.A., J.B., C.Z., and A.T. are employees of First Health Pharmaceuticals B.V.