CRISPR/Cas9在清除潜伏HIV前病毒基因组中的研究进展

抗反转录病毒疗法(ART)是目前治疗艾滋病(AIDS)的首选方法,因无法清除整合到CD4~+T细胞染色体上的艾滋病病毒(HIV)前病毒基因,在停止ART治疗后,整合的HIV前病毒基因会随着T细胞的活化被激活,从而重新复制感染,因此HIV感染者/AIDS患者须终生使用抗病毒药物。成簇规律间隔短回文重复序列及其核酸酶Cas9(CRISPR/Cas9)系统,因其设计简单、操作方便,且无种属间限制,成为最具有发展前景的基因组定点编辑技术。本文就CRISPR/Cas9系统及消除潜伏的HIV前病毒基因中的研究进展进行综述。     

艾滋病治疗的研究进展

艾滋病抗病毒治疗(ART),现已取得很大成效。该病原为致死性疾病,现已成为一种可治可管理的传染病,全球艾滋病病毒感染者/艾滋病(HIV/AIDS)的病例虽仍多达3 800万,但有一半以上已经抗病毒治疗。除了药物治疗外,目前一些新技术新方法如基因组编辑等也已介入艾滋病的治疗,并且在人源化动物试验中业已取得很好的效果。不容置疑,艾滋病终究会被人类控制消除。但随着艾滋病抗病毒治疗的不断发展,最根本的问题也就是HIV潜伏库的问题日益突出,不论是分子治疗、组合治疗都存在这样的问题。因此,不断寻找新的潜伏病毒细胞的标记,缩小病毒潜伏库,是当前艾滋病治疗必须解决的课题。此外,尽管艾滋病的防治取得了很大成绩,但目前全球每天仍有近6 000例HIV/AIDS感染的病例发生。因此,安全有效疫苗的研发,不论在预防领域、还是在临床治疗方面,都有其积极的意义。     

AIDS的新发现

CD_4“记忆亚组细胞”可藏匿HIV的新发现,甚至在血中不能检出病毒时也如此,说明有希望成为新的治疗AIDS的策略,但问题是如何用此发现抗击疾病。 去年研究人员总结提出,在感染HIV过程中很早就出现潜伏感染细胞的隐匿储藏,甚至当病人立即接受高效的抗逆转录病毒治疗(HAART)时也不能避免发生这种现象。 在日内瓦世界艾滋病讨论会上,美国马里兰州国家过敏和感染性疾病研究所主任Antony Fallci说:“在血中检出高水平的HIV时,病毒可能散布至静止的CD_4细胞中,从而形成一个潜伏的感染细胞库。研究人员还指出,在急性HIV感染发生10天后开始治疗也不能防止这种潜伏感染。     

吸毒成瘾HIV/AIDS患者抗逆转录病毒治疗的初步探讨

目的 评价国产艾滋病抗病毒药物治疗吸毒成瘾艾滋病病毒感染者/病人(HIV/AIDS)的疗效及对治疗时机的探讨. 方法 采用回顾性研究方法,调查随访2004～2007年在北京佑安医院确诊并经抗病毒治疗的吸毒成瘾HIV/AIDS患者114例,按照疾病进展将随访对象分成艾滋病组( AIDS)和HIV感染组(free of AIDS) ,所有患者均用3种抗病毒药物(奈韦拉平 司他夫定 拉米夫定)治疗,疗程48周.常规方法检测患者治疗前后血CD4 T淋巴细胞数,核酸序列扩增技术(NASBA)测定病毒载量. 结果 114例吸毒成瘾HIV/AIDS患者CD4细胞数平均增加(182.39±90.70)个/mm3;其中35例吸毒成瘾HIV/AIDS患者中85.71%病毒载量下降至50 copies/ml以下, 下降2.5个Log数;艾滋病组与HIV感染组治疗后3、6、9和12个月CD4 T淋巴细胞差异有统计学意义(P＜0.05);治疗6个月后,HIV感染组病毒载量下降趋势较艾滋病组明显,但治疗12个月后 HIV感染组病毒载量较艾滋病组有反弹现象. 结论 吸毒成瘾HIV/AIDS患者选用国产艾滋病抗病毒药物奈韦拉平 司他夫定 拉米夫定治疗取得良好效果,并且对艾滋病患者的疗效好于HIV感染者.     

影响HIV/AIDS人群死亡因素研究进展

回顾了目前全球及我国艾滋病流行与死亡状况,并通过检索1990年以来国内外关于艾滋病病毒感染者/艾滋病(HIV/AIDS)病人死亡影响因素研究的文献报道,发现影响HIV/AIDS人群死亡的主要因素有:感染者社会人口学特征、HIV感染途径、AIDS诊断时间、HAART治疗情况、CD 4T细胞数、经济发展状况、非艾滋病相关死亡及其他因素等.     

HIV感染与衰弱及认知功能障碍关系的研究进展

随着艾滋病病人数不断增加,日益加重的疾病负担已成为全球医疗卫生系统面临的重大挑战。艾滋病病毒(HIV)感染可导致许多老年相关疾病提前发生,其中衰弱和认知功能障碍与年龄相关的多种不良临床结局如跌倒、骨折、死亡等密切相关。本文综述了HIV感染者/艾滋病(AIDS)病人(简称HIV/AIDS病人)衰弱与认知功能障碍的相关关系研究进展,HIV/AIDS病人相比于非HIV/AIDS病人,衰弱与认知功能障碍的发生率更高,危害更显著。衰弱对认知功能障碍发生发展可能存在促进作用,但具体机制尚需进一步研究。了解HIV/AIDS病人衰弱与认知功能障碍的相关关系及其影响对临床医务人员开展相关研究与干预具有重要意义。     

HIV相关免疫激活及炎症发生机制研究进展

艾滋病病毒(HIV)相关的免疫激活及炎症反应贯穿于整个感染及治疗过程,因而导致患者易出现免疫重建不全及非艾滋病(AIDS)相关并发症。抗HIV药物的应用使艾滋病已从一个致死性疾病转变为一种慢性疾病,而异常免疫激活及炎症反应在艾滋病疾病进展中越来越受到关注。HIV相关的免疫激活与病毒储存库的持续存在,肠道菌群移位,调节性T细胞减少及合并或继发其他病毒感染有关。NF-κB信号,Caspase诱导的细胞焦亡/凋亡,干扰素信号,Toll样受体信号及各个调节通路之间的复杂的网络调控共同介导了HIV感染的炎症发生过程。了解HIV相关免疫激活及炎症调节机制,有助于合理使用免疫及炎症通路抑制剂为HIV感染者/AIDS病人的治疗提供新的思路。     

艾滋病与结核病双重感染的研究概况

HIV/AIDS的流行导致结核病(TB)的重新出现,而TB是HIV/AIDS发病和死亡的首要诱因。AIDS和TB相互促进,共同消耗,TB可能加速HIV感染到发病,而HIV感染也会加速TB进展。文章就艾滋病和结核病的相关问题结合文献资料进行阐述,希望对艾滋病和结核病预防、治疗的深入研究有益。     

HIV-1潜伏感染及功能性治愈

尽管高效抗反转录病毒治疗(HAART)可有效控制艾滋病(AIDS)病人体内的艾滋病病毒1型(HIV-1)的复制,但却无法根除潜伏感染的病毒,这成为当前艾滋病治疗的主要难点之一。研究HIV-1在宿主细胞内建立和维持潜伏的分子细胞学机制,有助于发现新的抗病毒靶点和发展新的抗病毒治疗策略。近年来对HIV感染者/AIDS病人提出功能性治愈策略,相关的免疫或基因治疗手段被相继提出,部分策略已处于临床试验阶段。该文对HIV-1潜伏感染机制和功能性治愈相关研究进展进行简要综述。     

利用混合效应线性模型分析甘肃省HIV/AIDS病人HAART后CD_4~+T淋巴细胞的变化

目的了解甘肃省接受高效抗反转录病毒治疗(HAART)的艾滋病(AIDS)病人CD+4T淋巴细胞(简称CD4细胞)的变化趋势,分析不同性别、年龄、感染途径治疗人群的治疗效果是否存在差异。方法利用SPSS 19.0描述艾滋病病毒(HIV)感染者/AIDS病人(简称HIV/AIDS病人)CD4细胞在治疗后5年内不同时间点上的分布情况,使用混合效应线性模型拟合CD4细胞计数与性别、年龄、感染途径等因素之间的关系。结果选取103例HIV/AIDS病人,男性占67.96%,女性占32.04%;治疗开始年龄以21~50岁为主,占86.41%;感染途径以性接触传播为主,占68.93%。开始治疗前病人CD4细胞中位数为156个/μL,治疗1、2、3、4、5年后,CD4细胞中位数分别为290个/μL、309个/μL、344个/μL、347个/μL、525个/μL。CD4细胞计数与治疗时间和开始治疗时CD4细胞水平正相关;性别和治疗开始年龄没有显著性差异;经男男性行为和血液途径感染的艾滋病病人治疗效果存在统计学差异(P0.05)。结论甘肃省接受HAART治疗的艾滋病病人在5年内CD4细胞计数有上升趋势,男男性行为感染者的治疗效果较经血液感染者好。     

AIDS: immunologic abnormalities following human immunodeficiency virus infection

Following human immunodeficiency virus (HIV) infection, there is an ordered progression of immunologic abnormalities that results from the selective infection of the T4 helper/inducer subset of T lymphocytes. The loss of helper T-cell function disrupts both the cellular and humoral aspects of the immune response. The T lymphocytes decrease in both number and function. The peripheral blood B lymphocytes demonstrate marked polyclonal activation and are unable to mount a serologic response to new antigens. The infected monocytes and macrophages serve as reservoirs for HIV and act as vehicles that transport the virus to target organs. Decreased activity of natural killer cells may promote progression of acquired immunodeficiency syndrome (AIDS). Factors that suppress the reaction of T and B lymphocytes to stimuli have been identified in the sera of AIDS patients. In conclusion, HIV infection causes progressive dysfunction and destruction of the entire immune system, resulting in severe opportunistic infections, neoplasms, and shortened survival of AIDS patients.     

Sources of data for improved surveillance of HIV/AIDS in China

The objective of this paper is to describe the evolution of human immunodeficiency virus/acquired immunodeficiency syndrome surveillance in mainland China, with a focus on reviewing the sources of data being used for improved surveillance of HIV/AIDS. We review the development of HIV/AIDS surveillance and its multiple data sources to monitor the dynamics of HIV/AIDS in China. The surveillance system for HIV/AIDS in China was initiated in 1986. It has evolved in three stages: (1) passive surveillance, (2) HIV sentinel surveillance with coexisting active surveillance and passive surveillance, and (3) comprehensive surveillance. In parallel with the evolution of the surveillance system itself, the HIV epidemic in China has gone through increasing stages of complexity, through an Introduction Phase, a Spreading Phase, and a Rapidy Spreading Phase. More reliable data from improved surveillance suggest that the HIV/AIDS epidemic is expanding in China. HIV infections among 2005 estimates remain concentrated among injection drug users (IDUs), those buying and selling sex, and men who have sex with men. Better HIV/AIDS surveillance synthesizes multiple data sources to provide a more accurate picture of the dynamics of specific HIV/AIDS circumstances in different areas of China. Improved surveillance is meaningful insofar as data are used to implement more effective HIV prevention programs in China. Support for surveillance and strategic analyses can enable policy decision makers to make more effective program choices and mobilize adequate resources to contain HIV.     

Approaches to an understanding of pathogenetic mechanisms in AIDS

AIDS, presumably caused by the human retrovirus, human immunodeficiency virus (HIV), is a disease with multiple pathologies, most of which are the consequence of a profound immunodeficiency. The first two sections of this review focus primarily on the normal development and function of the cells of the immune system and the known abnormalities that occur in this system in AIDS patients. Very little is known of the pathogenesis, in humans, of the four major clinical manifestations of AIDS--immunodeficiency, encephalopathy, Kaposi's sarcoma, and lymphoma. Because most pathologic studies derive from autopsy findings in terminal AIDS patients, it has been difficult to track the course of HIV infection from the time of initial contact with the virus through the evolution of the disease. Therefore, the final section of this review focuses on actual and potential animal models of AIDS and how such models might be valuable for studies on the pathogenesis of the disease, the development of relevant vaccines, and the testing of potential therapies.     

Experimental Systems for Measuring HIV Latency and Reactivation

The final obstacle to achieving a cure to HIV/AIDS is the presence of latent HIV reservoirs scattered throughout the body. Although antiretroviral therapy maintains plasma viral loads below the levels of detection, upon cessation of therapy, the latent reservoir immediately produces infectious progeny viruses. This results in elevated plasma viremia, which leads to clinical progression to AIDS. Thus, if a HIV cure is ever to become a reality, it will be necessary to target and eliminate the latent reservoir. To this end, tremendous effort has been dedicated to locate the viral reservoir, understand the mechanisms contributing to latency, find optimal methods to reactivate HIV, and specifically kill latently infected cells. Although we have not yet identified a therapeutic approach to completely eliminate HIV from patients, these efforts have provided many technological breakthroughs in understanding the underlying mechanisms that regulate HIV latency and reactivation in vitro. In this review, we summarize and compare experimental systems which are frequently used to study HIV latency. While none of these models are a perfect proxy for the complex systems at work in HIV+ patients, each aim to replicate HIV latency in vitro.     

Practicing HIV/AIDS community-based research

Although community-based research (CBR) is gaining popularity, especially within the field of HIV/AIDS research, there is a paucity of practical models or frameworks designed to guide researchers and community members. Within the present paper the author presents a ten-stage model of conducting CBR that emerged from two HIV/AIDS CBR studies that were conducted in Alberta, Canada. The main strengths and challenges to conducting HIV/AIDS CBR are also explored. Living a life with HIV has changed dramatically over the past few decades. There have been notable improvements in medical technology and treatment, resulting in increased quality and duration of life (Volberding, 1998; Wong-Staal, 1997) as well as improvements in psychosocial interventions leading to improved mental health services (Grinstead & Van Der Straten, 2000; Hoffman, 1996; Sarwer & Crawford, 1994; Schaffner, 1994). Perhaps most significant has been the astonishing community rallying and social support networks that have occurred among individuals living with HIV and AIDS (Roy & Cain, 2001). People living with HIV and AIDS have demonstrated their resilience and positive outlooks through developing a multitude of community connections and projects. These organizational groups have engaged in HIV peer counselling at community-based organizations, fund raising programs, board involvement in community agency organizations and HIV/AIDS national committees, as well as volunteer work in many settings. There has also been a recent focus on CBR, which includes having individuals living with HIV and AIDS, people vulnerable to HIV infection or other stakeholders in HIV/AIDS issues become partners in research projects with academic or trained researchers (Health Canada, 2002).     

Human immunodeficiency virus and the gastrointestinal tract

Human immunodeficiency virus (HIV) is a retrovirus infecting CD4 positive cells, causing profound immunosuppression and eventually manifesting clinically as the acquired immunodeficiency syndrome (AIDS). The cells principally infected by HIV are T4 (helper) lymphocytes and macrophages. The eventual loss of helper cell function is the prime reason for immunodeficiency, which renders the individual susceptible to opportunistic infections. Virtually every organ system in the body can be affected clinically during the course of HIV infection. The gastrointestinal tract is a major target and the physiological sequelae are an important cause of morbidity and mortality. The pathophysiology of intestinal infection is not yet fully understood but two main mechanisms have been postulated. The first is reduced intestinal immunity resulting in chronic opportunistic infections, which themselves cause altered intestinal function. The second is that HIV per se affects the intestinal mucosa, causing malfunction. The mechanisms by which the latter occurs are controversial but may result from either direct infection of mucosal epithelial cells or from macrophages within the mucosa. Reports have documented the presence of the HIV genome in both epithelial argentochromaffin cells and macrophages. In addition, profound degeneration of intrinsic jejunal autonomic neurones has been demonstrated but the functional significance of such denervation is as yet unknown. The clinical stage of HIV infection at which intestinal mucosal immunity fails is, by definition, when opportunistic infection occurs (that is, clinical progression to stage 4 disease, namely AIDS) but detailed knowledge of the aetiology of intestinal immune failure is lacking. However, protection of intestinal mucosal surfaces with antibodies against HIV, induced by vaccination using the oral or rectal route, is an area of great interest. The major site of entry of HIV is thought to be via the intestinal tract and thus protection of its surfaces may be crucial in preventing infection.     

Improving survival following AIDS in Australia, 1991-1996. National HIV Surveillance Committee

OBJECTIVE: To describe the pattern of survival following AIDS. DESIGN: National surveillance for AIDS diagnoses. METHODS: AIDS cases in adults/adolescents (aged 13 years or older at AIDS diagnosis) and deaths following AIDS were notified to the national HIV surveillance centre by the diagnosing doctor through State/Territory health authorities. The date of last medical contact for each case living with AIDS was updated annually. RESULTS: By 30 June 1999, 4814 AIDS cases, diagnosed in Australia in 1991-1996, and 3193 deaths following AIDS had been notified to the National AIDS Registry. Median survival following AIDS was 17.7 months. Survival following AIDS increased from 16.0 months in 1991 to 27.7 months in 1996. Factors independently associated with improved survival were year of AIDS diagnosis, late HIV diagnosis, CD4+ cell count greater than 50 x 10(6) cells/l, age of less than 45 years and presentation with Pneumocystis carinii pneumonia only or Kaposi's sarcoma only. The risk of death declined over time when the initial AIDS-defining illness was Pneumocystis carinii pneumonia only [adjusted hazard ratio (AHR) = 0.91, P < 0.0005]; other opportunistic infections (AHR, 0.88; P < 0.0005); Kaposi's sarcoma only (AHR, 0.92; P = 0.025); and central nervous system conditions (HIV encephalopathy, cryptococcosis, toxoplasmosis) (AHR, 0.92; P = 0.012). No time trend was observed for survival following diagnoses of non-Hodgkin's lymphoma or other multiple illnesses. CONCLUSIONS: Survival following AIDS has improved in Australia, especially among cases diagnosed in 1995 and 1996. Temporal improvements in survival following AIDS were coincident with the introduction of combination antiretroviral treatment for HIV infection and suggest that treatment is effective in limiting disease progression among people with advanced HIV infection.