HIV therapy最新文献

英文中文

Rituximab therapy for HIV-associated multicentric Castleman disease 利妥昔单抗治疗hiv相关多中心Castleman病

HIV therapy

Pub Date : 2010-05-04 DOI: 10.2217/HIV.10.17

O. Veraitch, M. Bower, D. Shackleton, J. Stebbing

HIV-associated multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder with marked systemic symptoms attributed to cytokine disarray. Many therapeutic approaches conducted in small series of patients have often proved unsuccessful. Rituximab is a chimeric monoclonal antibody that has been extensively used for B-cell lymphomas and autoimmune disorders. The use of rituximab for HIV–MCD now derives from a collection of case reports, case series and two clinical trials, which has led to rituximab being considered as the gold standard therapy for HIV–MCD. Rituximab infusions have been reported to be well tolerated in most patients with mild-to-moderate infectious complications being the most commonly reported toxicity. The most significant adverse event of rituximab therapy for HIV–MCD is Kaposi sarcoma progression. Further work is required to increase our understanding of the disease process to help refine the optimal therapy for this aggressive disease.

hiv相关的多中心Castleman病(MCD)是一种罕见的淋巴细胞增生性疾病，具有明显的全身症状，归因于细胞因子紊乱。许多在小范围患者中进行的治疗方法往往被证明是不成功的。利妥昔单抗是一种嵌合单克隆抗体，已广泛用于b细胞淋巴瘤和自身免疫性疾病。目前，利妥昔单抗治疗HIV-MCD的使用源于一系列病例报告、病例系列和两项临床试验，这使得利妥昔单抗被认为是HIV-MCD的金标准疗法。据报道，利妥昔单抗输注在大多数患者中耐受性良好，轻至中度感染并发症是最常见的毒性报道。利妥昔单抗治疗HIV-MCD最显著的不良事件是卡波西肉瘤进展。需要进一步的工作来增加我们对疾病过程的理解，以帮助改进这种侵袭性疾病的最佳治疗方法。

引用次数: 3

Dual infection with HIV‑1 and HIV‑2: double trouble or destructive interference? HIV - 1和HIV - 2双重感染:双重麻烦还是破坏性干扰?

HIV therapy

Pub Date : 2010-05-04 DOI: 10.2217/HIV.10.26

T. D. Silva, C. V. Tienen, S. Rowland-Jones, M. Cotten

HIV-1 and HIV-2 are two related retroviruses and, in regions where both infections are endemic, HIV-1/2 dual infection can occur. Several important questions arise about the interplay between these two viruses in a single host, including: what is the potential for HIV-1–HIV-2 recombinants to form, are there synergistic or inhibitory mechanisms that result in distinct viral replication dynamics when compared with HIV-1 or HIV-2 monoinfected individuals and what are the factors to consider when choosing antiretroviral regimes in HIV-1/2 dual-infected individuals? We summarize the relevant evidence to answer these questions, as well as indentify trends in prevalence and how the natural history of HIV-1/2 dual infection differs from that of HIV-1 or HIV-2 monoinfection. The epidemiological and in vitro evidence pertaining to the question of whether HIV-2 infection may protect against HIV-1 superinfection will also be addressed.

HIV-1和HIV-2是两种相关的逆转录病毒，在两种感染都流行的地区，可能发生HIV-1/2双重感染。关于这两种病毒在单一宿主中的相互作用，出现了几个重要的问题，包括:HIV-1 - HIV-2重组体形成的可能性是什么，与HIV-1或HIV-2单感染个体相比，是否存在导致不同病毒复制动力学的协同或抑制机制，以及在HIV-1/2双感染个体中选择抗逆转录病毒方案时应考虑哪些因素?我们总结了相关证据来回答这些问题，并确定流行趋势，以及HIV-1/2双重感染的自然历史与HIV-1或HIV-2单感染的不同之处。与HIV-2感染是否可以预防HIV-1重复感染有关的流行病学和体外证据也将得到解决。

引用次数: 26

Insights into the functions of a molecular Swiss army knife: the intasome structure reveals inhibitor action 洞察分子瑞士军刀的功能:侵入体结构揭示抑制剂的作用

HIV therapy

Pub Date : 2010-05-04 DOI: 10.2217/HIV.10.21

F. Christ

Evaluation of: Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P: Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464(7286), 232–236 (2010). During HIV replication, integrase is responsible for the integration of the cDNA copy of the viral RNA genome into the host chromatin. In the recent history of anti-HIV therapy integrase has become an established drug target for HAART, but development of second-generation integrase inhibitors has been hampered by the lack of structural information. Hare et al. have now described the full-length integrase structure of a distant cousin of HIV-1, the prototype foamy virus. This insight into the mechanism of catalysis will boost the rational design of second-generation strand-transfer inhibitors.

haare S, Gupta SS, Valkov E, Engelman A, Cherepanov P:逆转录病毒侵入体组装和DNA链转移抑制的评价。Nature 464(7286)， 232-236(2010)。在HIV复制过程中，整合酶负责将病毒RNA基因组的cDNA拷贝整合到宿主染色质中。在最近的抗hiv治疗历史中，整合酶已成为HAART的既定药物靶点，但由于缺乏结构信息，第二代整合酶抑制剂的开发一直受到阻碍。Hare等人现在已经描述了HIV-1的远亲——泡沫病毒的原型——的全长整合酶结构。这种对催化机制的深入了解将促进第二代链转移抑制剂的合理设计。

引用次数: 0

Genotypic determination of HIV-1 tropism in the clinical setting 临床环境中HIV-1嗜性的基因型测定

HIV therapy

Pub Date : 2010-05-04 DOI: 10.2217/HIV.10.15

L. C. Swenson, R. Boehme, A. Thielen, R. McGovern, P. Harrigan

HIV enters cells via the CD4 receptor and a coreceptor, generally CCR5 or CXCR4. The specific coreceptor used by a patient’s virus is referred to as its tropism. Tropism testing is necessary prior to treatment with CCR5 antagonist medication to rule out the presence of CXCR4-using (X4) virus, with the phenotypic Trofile™ assay being the most commonly used test for HIV coreceptor usage. Genotypic tropism testing may offer some practical advantages to phenotypic tropism testing and Trofile. Genotypic tropism assays are typically based on sequencing the V3 loop of HIV env and analysis using bioinformatic algorithms to infer the likely coreceptor usage of the virus. Genotypic methods have been refined and improved over the years and have recently been used as retrospective (and occasionally prospective) screening tools for treatment with CCR5 antagonist medication, such as maraviroc. Alternative approaches to genotypic tropism testing include heteroduplex tracking assays, ‘deep’ V3 sequencing and testing of c...

HIV通过CD4受体和一种辅助受体(通常是CCR5或CXCR4)进入细胞。病人的病毒所使用的特定的辅助受体被称为其趋向性。在使用CCR5拮抗剂治疗之前，有必要进行趋向性检测，以排除使用cxcr4的(X4)病毒的存在，表型Trofile™检测是HIV辅助受体使用的最常用检测。基因型趋向性检测相对于表型趋向性检测和性状分析具有一定的实际优势。基因型趋向性分析通常基于对HIV环境的V3环进行测序，并使用生物信息学算法进行分析，以推断病毒可能的辅助受体使用情况。基因型方法经过多年的完善和改进，最近被用作CCR5拮抗剂治疗的回顾性(偶尔也是前瞻性)筛选工具，如马拉维洛克。基因型趋向性检测的替代方法包括异双工跟踪测定，“深度”V3测序和c…

引用次数: 4

Possible applications for replicating HIV 1 vectors. 复制HIV 1载体的可能应用。

HIV therapy

Pub Date : 2010-05-01 DOI: 10.2217/hiv.10.20

Atze T Das, Rienk E Jeeninga, Ben Berkhout

Since its discovery some 25 years ago, much has been learned about HIV type 1 and the molecular details of its replication cycle. This insight has been used to develop lentiviral vector systems that have advantages over conventional retroviral vector systems. For safety reasons, the lentiviral vector systems are replication incompetent and the risk of generating a replication competent virus has been minimized. Nevertheless, there may be certain applications for replication competent HIV based vector systems, and we will review our activities in this particular field. This includes the generation of a conditionally replicating HIV 1 variant as a safe live attenuated virus vaccine, the construction of mini HIV variants as cancer selective viruses for virotherapy against leukemia, and the use of a conditionally live anti HIV gene therapy vector. Although safety concerns will undoubtedly remain for the use of replication competent HIV based vector systems, some of the results in cell culture systems are very promising and warrant further testing in appropriate animal models.

自从它在25年前被发现以来，人们对1型艾滋病毒及其复制周期的分子细节已经了解了很多。这一见解已被用于开发慢病毒载体系统，它比传统的逆转录病毒载体系统有优势。出于安全考虑，慢病毒载体系统是不具备复制能力的，产生具有复制能力的病毒的风险已经降到最低。尽管如此，基于HIV的载体系统可能会有一些复制能力的应用，我们将回顾我们在这一特定领域的活动。这包括产生有条件复制的HIV 1变异作为安全的减毒活疫苗，构建迷你HIV变异作为白血病病毒治疗的癌症选择性病毒，以及使用有条件活的抗HIV基因治疗载体。尽管使用具有复制能力的HIV载体系统无疑仍存在安全问题，但细胞培养系统的一些结果非常有希望，值得在适当的动物模型中进一步测试。

引用次数: 6

Comparison of scales to evaluate the progression of HIV-associated neurocognitive disorder. 评估hiv相关神经认知障碍进展的量表比较。

HIV therapy

Pub Date : 2010-05-01 DOI: 10.2217/hiv.10.23

Nishiena S Gandhi, Richard T Moxley, Jason Creighton, Heidi Vornbrock Roosa, Richard L Skolasky, Ola A Selnes, Justin McArthur, Ned Sacktor

AIM: First, to compare the characterization of neurocognitive deficits in milder stages of HIV-associated neurocognitive disorder (HAND) derived from existing dementia rating scales of the American Academy of Neurology (AAN) and Memorial Sloan Kettering (MSK) with the 2007 consensus ('Frascati') classification. Second, to identify potential sociodemographic and clinical predictors of HAND progression during 1-year follow-up. METHODS: 104 HIV-infected subjects in an existing cohort system were evaluated with a medical history, exam, neuropsychological test battery and functional assessments. The degree of HAND was rated using the AAN, MSK and Frascati scales. The degree of concordance among these scales was determined. In addition, 45 subjects were reassessed for changes in their neurocognitive status at 1-year follow-up. Associations between age, education, sex, depression ratings, substance abuse, race, hepatitis C serostatus, CD4 count and progression of HAND were examined. RESULTS: There was excellent concordance (gamma > 0.8) among the Frascati, MSK and AAN ratings. Subjects rated as having minor cognitive motor disorder on the AAN scale (n = 45) were evenly split between Frascati rating of asymptomatic neurocognitive impairment (n = 24) and mild neurocognitive disorder (n = 21). At 1-year follow-up of 45 subjects, 31% had worsened, 13% had improved and 56% were stable. Predictors of progression included age older than 50 years (odds ratio: 5.57; p = 0.013) and female gender (odds ratio: 3.13; p = 0.036). CONCLUSION: The Frascati HAND rating scale has excellent concordance with previous neurocognitive rating scales and can be used to better characterize milder stages of cognitive impairment. Older individuals and women appeared to be more likely to show neurocognitive progression.

目的:首先，比较来自美国神经病学学会(AAN)和纪念斯隆凯特林(MSK)现有痴呆评分量表与2007年共识(Frascati)分类的hiv相关神经认知障碍(HAND)轻度阶段神经认知缺陷的特征。其次，在1年随访期间确定潜在的社会人口学和临床预测因子。方法:对现有队列系统中的104名hiv感染者进行病史、检查、神经心理测试和功能评估。采用AAN、MSK和Frascati量表评定了手性程度。确定了这些量表之间的一致性程度。此外，在1年的随访中，对45名受试者的神经认知状态变化进行了重新评估。研究了年龄、教育程度、性别、抑郁程度、药物滥用、种族、丙型肝炎血清状态、CD4计数和HAND进展之间的关系。结果:Frascati、MSK和AAN评分具有极好的一致性(gamma > 0.8)。在AAN量表上被评为轻度认知运动障碍的受试者(n = 45)被平均分为无症状神经认知障碍的Frascati评分(n = 24)和轻度神经认知障碍(n = 21)。在45名受试者的1年随访中，31%恶化，13%改善，56%稳定。病情进展的预测因素包括年龄大于50岁(优势比:5.57;P = 0.013)和女性(优势比:3.13;P = 0.036)。结论:Frascati HAND评定量表与已有的神经认知评定量表具有良好的一致性，可更好地表征轻度认知障碍。老年人和女性似乎更有可能表现出神经认知方面的进展。

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引用次数: 41

The nucleocapsid protein of HIV-1 as a promising therapeutic target for antiviral drugs. HIV-1的核衣壳蛋白作为抗病毒药物的一个有前景的治疗靶点。

HIV therapy

Pub Date : 2010-03-10 DOI: 10.2217/HIV.10.3

V. Goldschmidt, L. Jenkins, H. Rocquigny, J. Darlix, Y. Mély

The nucleocapsid protein (NCp7) is a major HIV-1 structural protein that plays key roles in viral replication, mainly through its conserved zinc fingers that direct specific interactions with the viral nucleic acids. Owing to its high degree of conservation and critical functions, NCp7 represents a target of choice for drugs that can potentially complement HAART, thus possibly impairing the circulation of drug-resistant HIV-1 strains. Zinc ejectors showing potent antiretroviral activity were developed, but early generations suffered from limited selectively and significant toxicity. Compounds with improved selectivity have been developed and are being explored as topical microbicide candidates. Several classes of molecules inhibiting the interaction of NCp7 with the viral nucleic acids have also been developed. Although small molecules would be more suited for drug development, most molecules selected by screening showed limited antiretroviral activity. Peptides and RNA aptamers appear to be more promisin...

核衣壳蛋白(NCp7)是一种主要的HIV-1结构蛋白，主要通过其保守的锌指指导与病毒核酸的特异性相互作用，在病毒复制中起关键作用。由于其高度保守性和关键功能，NCp7代表了可能补充HAART的药物的选择靶标，从而可能损害耐药HIV-1毒株的循环。锌喷射器显示出强大的抗逆转录病毒活性，但早期代遭受有限的选择性和显著的毒性。选择性提高的化合物已被开发出来，并正在探索作为局部杀菌剂的候选物。抑制NCp7与病毒核酸相互作用的几类分子也被开发出来。虽然小分子分子更适合用于药物开发，但通过筛选选择的大多数分子显示出有限的抗逆转录病毒活性。多肽和RNA适体似乎更有希望。

引用次数: 33

HIV-associated chronic immune activation: current understandings and therapeutic intervention hiv相关的慢性免疫激活:目前的理解和治疗干预

HIV therapy

Pub Date : 2010-03-10 DOI: 10.2217/HIV.10.2

T. Vanderford, J. Adamski, G. Silvestri

The mechanisms by which HIV causes AIDS remain poorly understood. However, the generalized immune dysfunction associated with progressive HIV infection is clearly related to the levels of immune activation, which results in increased target cells for the virus, excessive apoptosis of uninfected T cells and, paradoxically, an impaired ability to control HIV replication. The causes of this chronic, aberrant immune activation are complex and are the consequences of both virus replication and the resultant immune damage and dysfunction. Of note, natural SIV hosts, which do not progress to AIDS despite lifelong infection, do not show chronic immune activation. Here we discuss the causes and consequences of the HIV-associated chronic immune activation, and potential therapeutic approaches to lower its impact.

艾滋病毒导致艾滋病的机制仍然知之甚少。然而，与进行性HIV感染相关的全面性免疫功能障碍显然与免疫激活水平有关，这导致病毒靶细胞增加，未感染T细胞过度凋亡，并且矛盾的是，控制HIV复制的能力受损。这种慢性、异常的免疫激活的原因是复杂的，是病毒复制和由此产生的免疫损伤和功能障碍的后果。值得注意的是，天然SIV宿主，尽管终生感染，但不会进展为艾滋病，也不会表现出慢性免疫激活。在这里，我们讨论了hiv相关慢性免疫激活的原因和后果，以及降低其影响的潜在治疗方法。

引用次数: 4

Prevention of mother-to-child HIV transmission in South Africa: the dawning of a new era 南非预防艾滋病毒母婴传播:新时代的曙光

HIV therapy

Pub Date : 2010-03-10 DOI: 10.2217/HIV.10.7

C. Horwood

In many HIV prevalent countries in sub-Saharan Africa death among HIV-infected mothers and their children is a major obstacle to achieving the millennium development goals (MDGs) for maternal and child mortality. In South Africa HIV/AIDS is the leading cause of maternal and child mortality and with HIV incidence estimated at 5% (per year) in 2006 life expectancy has decreased by more than 20 years since 1994. From 1990 onwards infant mortality has increased and maternal mortality has remained unchanged so without drastic action it is unlikely South Africa will achieve the two-thirds reduction in infant mortality or three-quarters reduction in maternal mortality required to reach MDGs 3 and 4 by 2015. (excerpt)

在撒哈拉以南非洲许多艾滋病毒流行的国家，感染艾滋病毒的母亲及其子女的死亡是实现降低孕产妇和儿童死亡率的千年发展目标的一个主要障碍。在南非，艾滋病毒/艾滋病是孕产妇和儿童死亡的主要原因，2006年艾滋病毒发病率估计为5%(每年)，自1994年以来，预期寿命减少了20多年。自1990年以来，婴儿死亡率上升，产妇死亡率保持不变，因此，如果不采取激烈行动，南非不可能实现到2015年实现千年发展目标3和4所要求的将婴儿死亡率降低三分之二或将产妇死亡率降低四分之三的目标。(摘录)

引用次数: 4

Genetic vaccination: engineering antiviral T-cell immunity through stem cells 基因疫苗:通过干细胞工程抗病毒t细胞免疫

HIV therapy

Pub Date : 2010-03-10 DOI: 10.2217/HIV.10.9

S. Kitchen, J. Zack

The human immune system is normally assidu‐ ous in controlling the environmental assaults that the body receives every day. Foreign anti‐ gens are typically targeted and cleared in a highly evolved and coordinated fashion by a variety of different cell types. Instances where this response fails and the pathogen is not cleared have important consequences for mor‐ bidity and mortality. This is certainly the case for HIV, where the infection is only partially controlled. The resultant persistence of the virus established after primary infection is an indica‐ tion of an ongoing battle between the immune response and the viruses’ ability to mutate and replicate. Ultimately, natural immune responses fail to prevent the establishment or clearance of infection with HIV in the vast majority of cases. Thus, there is a desperate need for alterna‐ tive strategies that augment natural immunity to HIV infection and that allow the immune system to specifically target and clear virally infected cells.

人体的免疫系统通常在控制人体每天受到的环境攻击方面起着辅助作用。外来的抗原通常以高度进化和协调的方式被各种不同的细胞类型靶向和清除。当这种反应失败且病原体未被清除时，会对发病率和死亡率产生重要影响。艾滋病毒的情况当然也是如此，它的感染只得到部分控制。初次感染后病毒的持续存在是免疫反应与病毒变异和复制能力之间持续斗争的标志。最终，在绝大多数情况下，自然免疫反应不能阻止艾滋病毒感染的建立或清除。因此，迫切需要一种替代策略来增强对HIV感染的天然免疫力，并允许免疫系统特异性地靶向和清除病毒感染的细胞。

引用次数: 0

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