HIV潜伏感染激活剂的研究进展

艾滋病是由人类免疫缺陷病毒(Human immunodeficiency virus,HIV)引起的人类最严重的单一病因疾病,以全身免疫系统严重损害为特征。高效抗逆转录病毒疗法(Highly active anti-retroviral therapy,HAART)的应用已经成功地将艾滋病从一种致死性疾病转变为慢性可控性疾病。但长期接受HAART治疗的艾滋病患者一旦停药,患者体内潜伏的HIV会迅速反弹。艾滋病无法彻底治愈的原因是患者体内HIV病毒潜伏储存库的存在。"Shock and kill"策略是使用HIV潜伏感染激活剂(Latency-reversing agents,LRAs)诱导潜伏HIV前病毒复制及表达,然后联合HAART将病毒一网打尽,同时由于细胞病变效应和/或HIV特征性免疫反应使潜伏细胞的半衰期大大缩短,最终达到功能性治愈的目的。因此,高效、安全且特异性促进潜伏库衰减的LRAs成为现今艾滋病治愈研究的热点。本文聚焦国内外前沿研究,对具有临床发展前景的HIV潜伏感染激活剂做一综述,为未来LRAs药物的研发指明方向。     

艾滋病的基因治疗策略及慢病毒载体

高活性的抗病毒治疗可以显著地降低艾滋病患者血浆中的HIV病毒载量,但对潜伏的病毒库无效.对HIV的基因治疗包括诱导HIV潜伏感染的休止的CD4 T记忆细胞增生,使潜伏的HIV激活进入复制循环,结合药物治疗和激活潜伏的HIV基因表达但并不诱导细胞增生,而是通过载体携带的基因使细胞凋亡,以清除HIV潜伏感染的细胞,利用载体携带目的基因治疗脑中的病毒.     

基因修饰的小鼠有助于AIDS研究

经基因工程产生的小鼠可为AIDS的研究提供动物模型并有助于科学家找到抗AIDS的有效药物。国立过敏性和感染性疾病研究所的John Leonard和同事一直从事HIV遗传信息的研究。HIV感染人类细胞时,病毒自身的酶复制遗传信息,从病毒RNA到DNA,这种DNA就整合到人类细胞的DNA中去,这种形式称为潜伏病毒,一旦细胞被激活,潜伏病毒就指导病毒蛋白的制造和装配。研究者将这种潜伏病毒的DNA注射到小鼠受精卵,再把受精卵植入小鼠子宫,在13个子代小鼠身上发现了HIV潜伏病毒的DNA,这些小鼠是健康的并分离不到病     

通过给血清学阳性者免疫接种以控制AIDS的展望

<正> 本文目的是建议一条对有关AIDS的现象学及其病因病毒(HIV)的思路,以及通过给HIV血清学阳性者免疫接种,以控制疾病和病因的方法。 就绝大多数病毒而言,免疫反应可将感染因子从宿主清除。但是某些病毒仍潜伏下来,例如:疱疹群病毒,甚至在免疫应答表达后,仍然以潜伏方式保存在神经细胞内,且随时可以活化。当病毒活化后,新形成的病毒或病毒蛋白从神经末稍释放出来,形成     

发现起动HIV增殖的蛋白

一些受染HIV的细胞保持沉默,即他们不产生病毒去感染其他细胞。这种细胞潜伏的原因不明,但美国宾西法尼亚大学(Philadelphia,PA)的研究人员发现了一种由活动HIV细胞产生并能将潜伏细胞变为活性病毒制造厂的蛋白。 研究人员从AIDS病病人外周血细胞和脑脊髓液中提纯了称为Vpr的蛋白,并将之放入在实验室中建立的潜伏细胞系中。Vpr诱导潜伏细胞积极地产生了HIV。然后,研究人员又将Vpr加入到受染病人的静止外周血细胞中,Vpr再次启动了HIV复制。     

人类免疫缺陷病毒解剖学病毒储存库与检测方法的研究进展

由于人类免疫缺陷病毒(human immunodeficiency virus,HIV)储存库的存在,获得性免疫缺陷综合征(acquired immunodeficiency syndrome,AIDS)患者即便接受高效抗反转录病毒治疗也无法完全清除体内的潜伏病毒.本文就HIV在人体内可能存在的解剖学储存库、病毒储存库...     

微小RNA对人类免疫缺陷病毒感染的影响: 飞向入侵者的子弹?

微小RNA(miRNA)是一类内源性小RNA,通过结合mRNA的3′非翻译区对基因进行转录后的调节,具有广泛的生物学功能.已有研究表明,宿主miRNA能调节人类免疫缺陷病毒(HIV)的基因表达,影响HIV的复制能力、感染性,并可能与HIV的潜伏有关.与此同时,HIV来源的病毒miRNA同样在病毒的生活史以及病毒与宿主的...     

造血干细胞中有HIV隐藏

虽然目前HIV/AIDS治疗试图控制疾病,但任何治疗的最终目的都是为根除病毒。遗憾的是,由于HIV在静息CD4+T细胞建立病毒潜伏储存库,所以该病毒的根除非常具有挑战性。最近,Carter等人发现HIV能感染造血干细胞(HSCs),因此,HIV的储存库比之前想象的更加持久更加稳固。     

HIV/AIDS的细胞治疗

获得性免疫缺陷综合征（AIDS）是由人类免疫缺陷病毒（HIV）感染引起的危险性极高的慢性传染病。高效抗逆转录病毒疗法（HAART）能够阻断正在进行的病毒复制而不能清除潜伏的病毒,目前尚无有效根治AIDS方法。免疫细胞在HIV/AIDS发展过程的不同阶段发挥着十分复杂的作用。细胞治疗是通过筛选表达抗HIV基因型的细胞或转染抗HIV基因、受体基因等方法获得抗HIV免疫细胞,并在体外进行扩增,将其转输给HIV/AIDS患者。细胞疗法与HAART等疗法有协同作用,促进HIV/AIDS的治疗。本文综述抗HIV-CAR T细胞、aTCR T细胞、负载HIV抗原的树突状细胞等在HIV/AIDS治疗中的应用及其疗效。     

microRNA在人类免疫缺陷病毒感染中的作用

microRNA(miRNA)对调控基因表达有着重要作用,病毒与宿主在miRNA水平存在着复杂的"对话"。研究显示,人类免疫缺陷病毒(HIV)可能编码病毒miRNA(vmiRNA),通过维持病毒潜伏、保护感染细胞免于凋亡或外力刺激下的细胞死亡等方式,在HIV病理过程中发挥重要作用。宿主miRNA则参与到了抗HIV的防御性机制中,但也面临HIV调控相应宿主miRNA、编码RNA沉默抑制物等多种阻力。深入研究HIV与宿主间miRNA水平上的动态相互作用,有助于进一步了解HIV的致病机理,开发新的治疗策略。     

Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips

Most HIV-infected patients when treated with combination antiretroviral therapy achieve viral loads that are below the current limit of detection of standard assays after a few months. Despite this, virus eradication from the host has not been achieved. Latent, replication-competent HIV-1 can generally be identified in resting memory CD4⁺ T cells in patients with “undetectable” viral loads. Turnover of these cells is extremely slow but virus can be released from the latent reservoir quickly upon cessation of therapy. In addition, a number of patients experience transient episodes of viremia, or HIV-1 blips, even with suppression of the viral load to below the limit of detection for many years. The mechanisms underlying the slow decay of the latent reservoir and the occurrence of intermittent viral blips have not been fully elucidated. In this study, we address these two issues by developing a mathematical model that explores a hypothesis about latently infected cell activation. We propose that asymmetric division of latently infected cells upon sporadic antigen encounter may both replenish the latent reservoir and generate intermittent viral blips. Interestingly, we show that occasional replenishment of the latent reservoir induced by reactivation of latently infected cells may reconcile the differences between the divergent estimates of the half-life of the latent reservoir in the literature.     

Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART

Whereas cells productively infected with human immunodeficiency virus type 1 (HIV-1) decay rapidly in the setting of highly active antiretroviral therapy (HAART), latently infected resting CD4(+) T cells decay very slowly, persisting for the lifetime of the patient and thus forming a stable reservoir for HIV-1. It has been suggested that the stability of the latent reservoir is due to low-level viral replication that continuously replenishes the reservoir despite HAART. Here, we offer the first quantitative study to our knowledge of inflow of newly infected cells into the latent reservoir due to viral replication in the setting of HAART. We make use of a previous observation that in some patients on HAART, the residual viremia is dominated by a predominant plasma clone (PPC) of HIV-1 not found in the latent reservoir. The unique sequence of the PPC serves as a functional label for new entries into the reservoir. We employ a simple mathematical model for the dynamics of the latent reservoir to constrain the inflow rate to between 0 and as few as 70 cells per day. The magnitude of the maximum daily inflow rate is small compared to the size of the latent reservoir, and therefore any inflow that occurs in patients on HAART is unlikely to significantly influence the decay rate of the reservoir. These results suggest that the stability of the latent reservoir is unlikely to arise from ongoing replication during HAART. Thus, intensification of standard HAART regimens should have minimal effects on the decay of the latent reservoir.     

Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy

Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the “critical efficacy” irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.     

Viral and latent reservoir persistence in HIV-1-infected patients on therapy

Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the "critical efficacy" irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.     

Residual Viremia in Treated HIV+ Individuals

Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. However, some residual virus remains, below the level of detection, in HIV-infected patients on ART. The source of this viremia is an area of debate: does it derive primarily from activation of infected cells in the latent reservoir, or from ongoing viral replication? Observations seem to be contradictory: there is evidence of short term evolution, implying that there must be ongoing viral replication, and viral strains should thus evolve. However, phylogenetic analyses, and rare emergent drug resistance, suggest no long-term viral evolution, implying that virus derived from activated latent cells must dominate. We use simple deterministic and stochastic models to gain insight into residual viremia dynamics in HIV-infected patients. Our modeling relies on two underlying assumptions for patients on suppressive ART: that latent cell activation drives viral dynamics and that the reproductive ratio of treated infection is less than 1. Nonetheless, the contribution of viral replication to residual viremia in patients on ART may be non-negligible. However, even if the portion of viremia attributable to viral replication is significant, our model predicts (1) that latent reservoir re-seeding remains negligible, and (2) some short-term viral evolution is permitted, but long-term evolution can still be limited: stochastic analysis of our model shows that de novo emergence of drug resistance is rare. Thus, our simple models reconcile the seemingly contradictory observations on residual viremia and, with relatively few parameters, recapitulates HIV viral dynamics observed in patients on suppressive therapy.     

Modeling HIV persistence, the latent reservoir, and viral blips

HIV-1 eradication from infected individuals has not been achieved with the prolonged use of highly active antiretroviral therapy (HAART). The cellular reservoir for HIV-1 in resting memory CD4⁺ T cells remains a major obstacle to viral elimination. The reservoir does not decay significantly over long periods of time but is able to release replication-competent HIV-1 upon cell activation. Residual ongoing viral replication may likely occur in many patients because low levels of virus can be detected in plasma by sensitive assays and transient episodes of viremia, or HIV-1 blips, are often observed in patients even with successful viral suppression for many years. Here we review our current knowledge of the factors contributing to viral persistence, the latent reservoir, and blips, and mathematical models developed to explore them and their relationships. We show how mathematical modeling has helped improve our understanding of HIV-1 dynamics in patients on HAART and of the quantitative events underlying HIV-1 latency, reservoir stability, low-level viremic persistence, and emergence of intermittent viral blips. We also discuss treatment implications related to these studies.     

Impact of Latently Infected Cells on Strain Archiving Within HIV Hosts

Latently infected cells are a barrier to HIV eradication on therapy due to long half-lives of between 6 and 44 months. The mechanism behind this long term maintenance is unclear although bystander proliferation and asymmetric division have both been put forward for consideration in mathematical models. The latently infected cell reservoir seems to act as an archive for strains of HIV no longer dominant in the blood, such as wild-type virus when the individual is on therapy. This is particularly significant when patients wish to come off medication and wild-type virus re-emerges.We use a two target cell model capable of producing low-level viral load on therapy and include latent cells and two strains of virus, wild-type and drug resistant, to investigate the impact of two possible mechanisms of latent cell reservoir maintenance on strain archiving. We find that although short term (less than a year) archiving of viral strains is possible in a model with no mechanism for reservoir maintenance, both bystander proliferation and asymmetric division of latent cells allow archiving to occur over much longer timescales (2 or more years). We suggest that regardless of the mechanism involved, latent cell reservoir maintenance allows strain archiving to occur. We interpret our results for clinical consideration.     

Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype

Latent human immunodeficiency virus type 1 (HIV-1) persists even in patients treated with antiretroviral therapy. New treatment strategies are therefore needed to eradicate this latent viral reservoir without reducing immune cell function. We characterize the interleukin-7 (IL-7)-induced stimulation of primary human T cells and thymocytes and demonstrate, using the SCID-hu model, that IL-7 induces substantial expression of latent HIV while having minimal effects on the cell phenotype. Thus, IL-7 is a viable candidate to activate expression of latent HIV and may facilitate immune clearance of latently infected cells.     

HIV病毒潜伏库的形成机制和对策挑战

长期以来,病毒潜伏库(latent viral reservoir,LVR)的存在严重阻碍了AIDS的有效治疗,LVR无法被人体免疫系统识别,高效抗逆转录病毒疗法(highly active antiretroviral therapy, HAART)对其无效,一旦中断抗病毒治疗,患者会出现快速耐药和病毒血症反弹.截至...