Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication.
Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication.
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DOI：
10.1186/1742-4690-10-120
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发表时间：
2013-10-24
期刊：
影响因子：
3.3
通讯作者：
Dougherty JP
中科院分区：
文献类型：
--
作者：
Miller LK;Kobayashi Y;Chen CC;Russnak TA;Ron Y;Dougherty JP
现有的高效抗逆转录病毒疗法 (HAART) 可以有效控制 1 型人类免疫缺陷病毒 (HIV-1) 感染个体中的病毒复制，但不能完全根除感染，至少部分原因是潜伏感染细胞的持续存在。正在积极推行消除潜伏性 HIV-1 感染的一项策略，涉及将潜伏性拮抗剂与 HAART 相结合的疗法。然而，这些类型药物之间不一致的药代动力学可能会在某些组织内产生活跃的病毒复制位点，而这些组织可能不受HAART的影响。初步的反向遗传筛选表明蛋白酶体可能参与潜伏状态的维持。这促使人们进行测试以确定蛋白酶体抑制剂（PI）对潜伏感染细胞的影响。实验表明，PI 可以有效激活多种模型系统（包括原代 T 细胞模型）中的潜伏 HIV-1，从而将 PI 定义为一类新型 HIV-1 潜伏拮抗剂。扩展之前报告的实验，还证实 PI 可以抑制病毒复制。此外，还可以证明 PI 可作为 HIV-1 的双功能拮抗剂。数据表明，PI 激活潜伏的原病毒，随后降低病毒滴度并促进激活细胞产生缺陷病毒体。这些结果证明了HIV-1双功能拮抗剂可以被开发出来，并且有能力确保抗潜伏和抗复制功能的精确组织重叠，这对于考虑未来旨在清除病毒的药物疗法具有重要意义。
Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART. A preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells. These results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.
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DOI：
10.1097/qad.0b013e32832ec1dc
发表时间：
2009-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
Archin NM;Keedy KS;Espeseth A;Dang H;Hazuda DJ;Margolis DM
通讯作者：
Margolis DM
影响因子：
11.8
作者：
Antinori, A;Perno, CF;Piscitelli, SC
通讯作者：
Piscitelli, SC
影响因子：
30.3
作者：
Goffinet, Christine;Allespach, Ina;Keppler, Oliver T.
通讯作者：
Keppler, Oliver T.
影响因子：
4.8
作者：
Anzinger, Joshua J.;Olinger, Gene G.;Spear, Gregory T.
通讯作者：
Spear, Gregory T.
影响因子：
3.5
作者：
Fenical, William;Jensen, Paul R.;Palladino, Michael A.;Lam, Kin S.;Lloyd, G. Kenneth;Potts, Barbara C.
通讯作者：
Potts, Barbara C.