The importance of targeting HIV reservoirs: preclinical insights on current and potential therapeutic opportunities.
The importance of targeting HIV reservoirs: preclinical insights on current and potential therapeutic opportunities.
复制标题
针对艾滋病毒储存库的重要性：对当前和潜在治疗机会的临床前见解。
DOI：
10.1080/14728222.2019.1702971
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发表时间：
2019
影响因子：
5.8
通讯作者：
Cory,TheodoreJ
中科院分区：
文献类型：
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作者：
Cory,TheodoreJ
用于治疗HIV-1的抗逆转录病毒药物是过去30年来抗感染药物开发的最显著的成功故事之一。抗逆转录病毒药理学的进步已经改变了疾病进展，使许多及时开始治疗的人成为可管理的慢性疾病，没有感染对多种药物耐药的病毒，并且坚持服药。2016年的一项研究显示，接受抗逆转录病毒治疗的艾滋病毒感染者/艾滋病患者（PLWHA）的预期寿命显著改善，与艾滋病毒流行的最早时期相比，PLWHA和未感染艾滋病毒的人之间的预期寿命差距缩小了差距[1]。尽管有这些显著的改善，但迄今为止，HIV-1的治愈在很大程度上是难以捉摸的，只有一个长期的HIV-1功能性治愈，第二个病例缓解，希望功能性治愈[2，3]。虽然这两个案例非常令人兴奋，但这种方法存在相当大的成本、警告、担忧和风险，这限制了这种方法被广泛采用的能力。由于这些风险和成本，正在研究一些其他战略，作为打击HIV-1复制的手段。一般来说，这些策略分为两种一般方法：基于抗体的方案，以防止或控制病毒复制，以及药物相关的策略，以重新激活细胞库中的潜伏病毒，或靶向组织库中的病毒复制。虽然非常有趣，但基于抗体的策略在很大程度上超出了本文的重点。细胞储库策略是基于这样的一般前提，即HIV-1可以驻留在长寿命的潜伏感染细胞中，然后当细胞被重新激活时被重新激活。因此，这些策略的主要目标是重新激活潜伏的T细胞，然后杀死感染的细胞（休克和杀死），或者防止这些细胞重新激活（阻断和锁定）。第二种一般策略集中在病毒可以驻留的组织部位，并假定这些组织部位代表了阻止抗逆转录病毒药物到达这些部位的细胞的屏障。这些部位可以包括脑、淋巴结、肺和次级淋巴组织。因此，在这些组织部位可能存在低水平的病毒复制，一旦抗逆转录病毒治疗中断，就可以为病毒提供一个位置，然后传播并重新感染身体的其他部位。这两种一般性战略各有优缺点，目前正在制定战略，通过这些不同的办法来防止HIV-1的复制。
Antiretrovirals for the treatment of HIV-1 are one of the most remarkable success stories of anti-infective drug development of the last 30 years. Advancements in antiretroviral pharmacology has altered disease progression to that of a manageable chronic condition for many individuals who start therapy in a timely manner, are not infected with virus resistant to multiple drugs, and who are adherent with their medications. A 2016 study showed significant improvements in life expectancy in people living with HIV/AIDS (PLWHA) who were receiving antiretroviral care, and a narrowing of the gap in life expectancy between PLWHA and people who did not have HIV as compared to the earliest days in the HIV epidemic [1]. Despite these remarkable improvements, to date a cure for HIV-1 has largely been elusive, with only one long-term functional cure for HIV-1, and a second case in remission with hopes of a functional cure [2, 3]. While these two cases are extremely exciting, there are considerable costs, caveats, concerns, and risks associated with this approach, which limits the ability of this approach to be adopted wide scale. Due to these risks and costs, a number of other strategies are under investigation as a means to combat HIV-1 replication. Broadly speaking, these strategies fall into two general approaches: antibody-based regimens to either prevent or control viral replication, and drug related strategies to either reactivate latent virus in cellular reservoirs, or to target viral replication in tissue reservoirs. While extremely interesting, antibody-based strategies are largely outside the focus of this review. Cellular reservoir strategies are based on the general premise that HIV-1 can reside in long-lived latently infected cells, then be reactivated when the cell is reactivated. Thus, the primary goal of these strategies is to either reactivate latent T cells, then kill the infected cells (shock and kill), or to prevent these cells from reactivating (block and lock). A second general strategy focuses on tissue sites where the virus can reside, and posits that these tissue sites represent a barrier preventing antiretrovirals from reaching cells in these sites. These sites can include the brain, lymph nodes, lungs, and secondary lymphoid tissue. Thus, there may be low-level viral replication occurring in these tissue sites, which once antiretroviral therapy has been interrupted can provide a location for the virus to then spread and reinfect the rest of the body. Both of these general strategies have their merits and weaknesses, and strategies are under development to combat HIV-1 replication through these disparate approaches.