Aging and HIV/AIDS: pathogenetic role of therapeutic side effects.
Aging and HIV/AIDS: pathogenetic role of therapeutic side effects.
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DOI：
10.1038/labinvest.2013.142
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发表时间：
2014-02
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影响因子：
--
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老龄化和艾滋病毒/艾滋病的交集是一种隐现的“流行病中的流行病”。本文综述了艾滋病毒/艾滋病及其治疗如何导致早衰或机械地促成艾滋病毒相关的非艾滋病疾病（HANA）。通过核苷类逆转录酶抑制剂（NRTIs）、非核苷类逆转录酶抑制剂和被称为HAART（高活性抗逆转录病毒疗法）的蛋白酶抑制剂（pi）的联合治疗，HIV/AIDS患者的生存率显著提高。由于nrti和pi共同预防或减弱HIV-1复制，延长寿命，因此老年HIV/AIDS患者的数量相应增加。然而，在没有艾滋病毒/艾滋病的情况下，经常与衰老相关的疾病似乎在艾滋病毒/艾滋病患者中过早发生。有助于解释生物衰老的理论包括氧化应激（线粒体氧化损伤超过抗氧化防御），染色体端粒缩短与相关的细胞衰老，以及层粘连蛋白A前体（核包膜蛋白）的积累。每一种情况都有可能因艾滋病毒/艾滋病、抗逆转录病毒治疗或两者兼而有之而增强或引起。抗逆转录病毒疗法已被证明能增强生物衰老过程中出现的事件。具体来说，抗逆转录病毒nrti会导致线粒体功能障碍、氧化应激和线粒体DNA缺陷，这些缺陷与HANA和衰老的特征相似。最近的临床证据表明，NRTI三磷酸诱导的端粒酶抑制导致端粒缩短，表明端粒酶逆转录酶（TERT）抑制是HIV/AIDS患者早衰的一个致病因素。PIs也可能在HIV/AIDS患者的早衰中起作用，因为它们会引起前纤层蛋白a的积累。总的来说，HAART的毒副作用可能类似并促进衰老事件，值得进行机制研究。
The intersection of aging and HIV/AIDS is a looming ‘epidemic within an epidemic.’ This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active anti-retroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies.
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