Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, United States.
Department of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United States.
Front Immunol. 2022 Dec 9;13:1033672. doi: 10.3389/fimmu.2022.1033672. eCollection 2022.
B cell lymphoma 2 (BCL-2) family proteins are involved in the mitochondrial apoptotic pathway and are key modulators of cellular lifespan, which is dysregulated during human immunodeficiency virus type 1 (HIV-1) and other viral infections, thereby increasing the lifespan of cells harboring virus, including the latent HIV-1 reservoir. Long-lived cells harboring integrated HIV-1 DNA is a major barrier to eradication. Strategies reducing the lifespan of reservoir cells could significantly impact the field of cure research, while also providing insight into immunomodulatory strategies that can crosstalk to other viral infections. Venetoclax is a first-in-class orally bioavailable BCL-2 homology 3 (BH3) mimetic that recently received Food and Drug Administration (FDA) approval for treatment in myeloid and lymphocytic leukemia. Venetoclax has been recently investigated in HIV-1 and demonstrated anti-HIV-1 effects including a reduction in reservoir size. Another immunomodulatory strategy towards reduction in the lifespan of the reservoir is Jak 1/2 inhibition. The Jak STAT pathway has been implicated in BCL-2 and interleukin 10 (IL-10) expression, leading to a downstream effect of cellular senescence. Ruxolitinib and baricitinib are FDA-approved, orally bioavailable Jak 1/2 inhibitors that have been shown to indirectly decay the HIV-1 latent reservoir, and down-regulate markers of HIV-1 persistence, immune dysregulation and reservoir lifespan and . Ruxolitinib recently demonstrated a significant decrease in BCL-2 expression in a human study of virally suppressed people living with HIV (PWH), and baricitinib recently received emergency use approval for the indication of coronavirus disease 2019 (COVID-19), underscoring their safety and efficacy in the viral infection setting. BCL-2 and Jak 1/2 inhibitors could be repurposed as immunomodulators for not only HIV-1 and COVID-19, but other viruses that upregulate BCL-2 anti-apoptotic proteins. This review examines potential routes for BCL-2 and Jak 1/2 inhibitors as immunomodulators for treatment and cure of HIV-1 and other viral infections.
B 细胞淋巴瘤 2 (BCL-2) 家族蛋白参与线粒体凋亡途径，是细胞寿命的关键调节剂，在人类免疫缺陷病毒 1 型 (HIV-1) 和其他病毒感染期间，细胞寿命被失调，从而增加了携带病毒的细胞的寿命，包括潜伏的 HIV-1 储存库。携带整合 HIV-1 DNA 的长寿细胞是根除的主要障碍。降低储存库细胞寿命的策略可能会对治愈研究领域产生重大影响，同时也为免疫调节策略提供了深入了解，可以与其他病毒感染相互作用。维奈托克是一种首创的口服生物可利用 BCL-2 同源性 3 (BH3) 模拟物，最近获得美国食品和药物管理局 (FDA) 批准用于治疗髓系和淋巴细胞白血病。维奈托克最近在 HIV-1 中进行了研究，并显示出抗 HIV-1 作用，包括减少储存库大小。另一种降低储存库寿命的免疫调节策略是 Jak 1/2 抑制。Jak STAT 途径已被牵连到 BCL-2 和白细胞介素 10 (IL-10) 的表达中，导致细胞衰老的下游效应。鲁索利替尼和巴瑞替尼是 FDA 批准的口服生物可利用的 Jak 1/2 抑制剂，已被证明可间接衰减 HIV-1 潜伏储存库，并下调 HIV-1 持续存在、免疫失调和储存库寿命的标志物 和 。鲁索利替尼最近在一项对 HIV 抑制的艾滋病毒感染者 (PWH) 的人体研究中显示出 BCL-2 表达的显著下降，而巴瑞替尼最近因治疗 2019 年冠状病毒病 (COVID-19) 获得紧急使用批准，强调了它们在病毒感染环境中的安全性和有效性。BCL-2 和 Jak 1/2 抑制剂可被重新用作免疫调节剂，不仅用于 HIV-1 和 COVID-19，还可用于其他上调 BCL-2 抗凋亡蛋白的病毒。本综述探讨了 BCL-2 和 Jak 1/2 抑制剂作为免疫调节剂用于治疗和治愈 HIV-1 和其他病毒感染的潜在途径。
