降低我国艾滋病患者病死率的几个关键措施

随着人类免疫缺陷病毒(HIV)感染者逐渐进入获得性免疫缺陷综合征(AIDS)期,我国HIV感染者病死人数逐渐增加,已超过结核病与狂犬病的病死人数,位居第1.如何降低HIV/AIDS患者的病死率是我国目前亟待解决的重要课题.针对我国HIV/AIDS患者的特点,应采用多种措施.其中关键为:落实患者对药物的依从性,优化抗病毒治疗方案;扩大抗病毒治疗覆盖面,以增加接受抗病毒治疗的患者;加大检测力度,早诊断和早治疗以延长患者寿命,改善预后;注意对患者并发症的治疗,并科学分析病死原因.这些措施的实施需要社会各界共同参与和努力.     

Use of simian immunodeficiency virus for vaccine research

Rhesus monkeys were immunized with purified, disrupted, noninfectious simian immunodeficiency virus (SIV) in adjuvant induced SIV neutralizing antibodies. Two of six previously vaccinated macaques were protected against infection when challenged with 200-1,000 animal infectious doses of uncloned, pathogenic SIV and both have remained free of signs of virus infection for 19 and 30 months. Prior vaccination appeared to be of benefit in decreasing the virus load and in delaying the onset of AIDS in animals that became infected. Nonetheless, two of four previously vaccinated monkeys that became infected following challenge eventually developed AIDS and died 505 and 538 days after infection. Thus, for a vaccine to be truly effective against AIDS, it may have to protect absolutely against initial infection.     

Epidemiology and the emergence of human immunodeficiency virus and acquired immune deficiency syndrome

Although acquired immune deficiency syndrome (AIDS) was first described in the USA in 1981, there is evidence that individual cases occurred considerably earlier in Central Africa, and serological and virological data show human immunodeficiency virus (HIV) was present in the Democratic Republic of Congo (DRC) as far back as 1959. It is likely that HIV-1 infection in humans was established from cross-species transmission of simian immunodeficiency virus of chimpanzees, but the circumstances surrounding this zoonotic transfer are uncertain. This presentation will review how causality is established in epidemiology, and review the evidence (a putative ecological association) surrounding the hypothesis that early HIV-1 infections were associated with trials of oral polio vaccine (OPV) in the DRC. From an epidemiological standpoint, the OPV hypothesis is not supported by data and the ecological association proposed between OPV use and early HIV/AIDS cases is unconvincing. It is likely that Africa will continue to dominate global HIV and AIDS epidemiology in the near to medium-term future, and that the epidemic will evolve over many decades unless a preventive vaccine becomes widely available.     

Kunjin virus replicon vectors for human immunodeficiency virus vaccine development

We have previously demonstrated the ability of the vaccine vectors based on replicon RNA of the Australian flavivirus Kunjin (KUN) to induce protective antiviral and anticancer CD8+ T-cell responses using murine polyepitope as a model immunogen (I. Anraku, T. J. Harvey, R. Linedale, J. Gardner, D. Harrich, A. Suhrbier, and A. A. Khromykh, J. Virol. 76:3791-3799, 2002). Here we showed that immunization of BALB/c mice with KUN replicons encoding HIV-1 Gag antigen resulted in induction of both Gag-specific antibody and protective Gag-specific CD8+ T-cell responses. Two immunizations with KUNgag replicons in the form of virus-like particles (VLPs) induced anti-Gag antibodies with titers of > or =1:10,000. Immunization with KUNgag replicons delivered as plasmid DNA, naked RNA, or VLPs induced potent Gag-specific CD8+ T-cell responses, with one immunization of KUNgag VLPs inducing 4.5-fold-more CD8+ T cells than the number induced after immunization with recombinant vaccinia virus carrying the gag gene (rVVgag). Two immunizations with KUNgag VLPs also provided significant protection against challenge with rVVgag. Importantly, KUN replicon VLP vaccinations induced long-lasting immune responses with CD8+ T cells able to secrete gamma interferon and to mediate protection 6 to 10 months after immunization. These results illustrate the potential value of the KUN replicon vectors for human immunodeficiency virus vaccine design.     

Use of Old World monkeys for acquired immunodeficiency syndrome research

Mangabeys, macaques, and baboons persistently infected with human immunodeficiency virus (HIV)-2 NIH-DZ demonstrated no signs of immunodeficiency disease after 6-11 months following seroconversion. Thus Old World monkeys provide an animal model to investigate the effects of passive immunization (anti-HIV-2 antibodies) on HIV infection in primates.     

全球人类免疫缺陷病毒疫苗研究的进展、挑战和我国的历史性机遇

经历第1代和第2代疫苗失败磨难后的人类免疫缺陷病毒(HIV)疫苗领域,终于在漫漫征途中看到了一线曙光。第1、2代联合疫苗在泰国开展RV144Ⅲ期临床试验,首次显示预防HIV感染的目标并非遥不可及。更为广谱的中和抗体及其晶体结构的获得、抗体基因的直接导入产生的免疫保护、嵌合型T细胞表位疫苗和复制型病毒载体疫苗的推进,为产生较RV144保护效果更好的疫苗提供了技术和策略支持。在国家科技重大专项的支持下,中国HIV疫苗联盟在合作攻关中推进创新性HIV疫苗的研究。全球和地区层面的科技合作,为中国HIV疫苗研究提供了实现跨越式发展的历史性机遇。     

Using human immunodeficiency virus type 1 sequences to infer historical features of the acquired immune deficiency syndrome epidemic and human immunodeficiency virus evolution

In earlier work, human immunodeficiency virus type 1 (HIV-1) sequences were analysed to estimate the timing of the ancestral sequence of the main group of HIV-1, the virus that is responsible for the acquired immune deficiency syndrome pandemic, yielding a best estimate of 1931 (95% confidence interval of 1915-1941). That work will be briefly reviewed, outlining how phylogenetic tools were extended to incorporate improved evolutionary models, how the molecular clock model was adapted to incorporate variable periods of latency, and how the approach was validated by correctly estimating the timing of two historically documented dates. The advantages, limitations, and assumptions of the approach will be summarized, with particular consideration of the implications of branch length uncertainty and recombination. We have recently undertaken new phylogenetic analysis of an extremely diverse set of human immunodeficiency virus envelope sequences from the Democratic Republic of the Congo (the DRC, formerly Zaire). This analysis both corroborates and extends the conclusions of our original study. Coalescent methods were used to infer the demographic history of the HIV-1 epidemic in the DRC, and the results suggest an increase in the exponential growth rate of the infected population through time.     

Xpert MTB/RIF在人类免疫缺陷病毒感染/艾滋病患者中诊断结核病的价值

为探讨利福平耐药结核分枝杆菌实时荧光定量核酸扩增检测技术(Xpert Mycobacterium tuberculosis/rifampicin,Xpert MTB/RIF)在人类免疫缺陷病毒感染/艾滋病(human immunodeficiency virus infection/acquired immunodeficiency syndrome,HIV/AIDS)患者中诊断结核病的价值,本研究回顾性分析了2018年1月1日—2020年12月31日复旦大学附属公共卫生临床中心感染与免疫科收治的801例HIV/AIDS合并疑似结核病患者的临床资料。801例患者中,657例进行了Xpert MTB/RIF、外周血结核感染T细胞斑点试验(tuberculosis T cell spot test,T-SPOT.TB)、抗酸染色涂片镜检和BACTEC MGIT 960液体培养等检测。以液体培养及菌型鉴定结果作为结核病诊断的“金标准”,确诊结核病92例,Xpert MTB/RIF、T-SPOT.TB、抗酸染色涂片镜检在HIV/AIDS患者中诊断结核病(包括肺结核和肺外结核)的灵敏度分别为72.8%、55.4%和69.6%,特异度分别为96.8%、90.3%和84.4%,与“金标准”行一致性检验,Kappa值分别为0.719 (P<0.01)、0.430(P<0.01)和0.424(P<0.01)。Xpert MTB/RIF检测502份呼吸道样本,结果显示其诊断肺结核的灵敏度和特异度分别为66.7%和96.0%;在痰涂片阳性和阴性的患者中,Xpert MTB/RIF诊断肺结核的灵敏度分别为77.4%和35.2%,特异度分别为87.7%和 97.8%。采用Xpert MTB/RIF检测343份肺外标本,结果显示其诊断肺外结核的灵敏度和特异度分别为63.3%和95.2%。以上结果提示,Xpert MTB/RIF在HIV/AIDS患者中诊断结核病(包括肺结核和肺外结核)具有较高的灵敏度和特异度,诊断肺结核的灵敏度高于肺外结核,因此推荐将其作为HIV/AIDS患者疑似结核病的首选检测方法。     

女性艾滋病患者的抗反转录病毒治疗与人类免疫缺陷病毒母婴阻断

自从对感染人类免疫缺陷病毒(HIV)的妊娠妇女实施抗反转录病毒治疗(ART)以预防母婴垂直传播以来,HIV母婴阻断成功率明显上升。而部分抗病毒药物,如依非韦伦和替诺福韦,也逐渐被证实用于妊娠期妇女对胎儿是安全的,这增加了HIV母婴阻断药物的选择范围。     

艾滋病痴呆综合征蛋白质组学的研究进展

艾滋病痴呆综合征(acquired immunodeficiency syndrome dementia complex, ADC)是由人类免疫缺陷病毒(human immunodeficiency virus,HIV)侵犯中枢神经系统,造成患者意识、行为和运动能力改变为主要临床表现的综合征。约50%的HIV感染者表现出不同形式的认知功能损伤。ADC的发病机制尚未完全阐明,诊断也无明确的病理和生化指标。目前,蛋白质组学技术以其高灵敏度和高通量的特点广泛应用于传染病研究。本文综述了近年来ADC蛋白质组学研究领域的进展,包括ADC蛋白质组学研究所用样品、蛋白质组学技术及其在ADC研究中的应用,为ADC的诊断和发病机制研究提供新思路。     

Human immunodeficiency virus/acquired immunodeficiency syndrome and tropical diseases: a Brazilian perspective

The paper summarizes recent findings on the epidemiology and pathogenesis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/Aids), highlighting the role of co-infections with major tropical diseases. Such co-infections have been studied in the Brazilian context since the beginning of the Aids epidemic and are expected to be more frequent and relevant as the Aids epidemic in Brazil proceeds towards smaller municipalities and the countryside, where tropical diseases are endemic. Unlike opportunistic diseases that affect basically the immunocompromised host, most tropical diseases, as well as tuberculosis, are pathogenic on their own, and can affect subjects with mild or no immunosuppression. In the era of highly active anti-retroviral therapies (HAART), opportunistic diseases seem to be on decrease in Brazil, where such medicines are fully available. Benefiting from HAART in terms of restoration of the immune function, putative milder clinical courses are expected in the future for most co-infections, including tropical diseases. On the other hand, from an ecological perspective, the progressive geographic diffusion of Aids makes tropical diseases and tuberculosis a renewed challenge for Brazilian researchers and practitioners dealing with HIV/Aids in the coming years.     

Detection of Cryptosporidium--specific coproantigen in human immunodeficiency virus/acquired immunodeficiency syndrome patients by using a commercially available immunoenzymatic assay

The aim of this study was to verify the occurrence of Cryptosporidium infection in 52 human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients (group 1) and 38 clinically healthy individuals (group 2) by using enzyme immunoassay (EIA). All fecal samples collected were submitted to the Baermann, Lutz and Ritchie methods, the Safranin/Methylene Blue, and Weber's chromotrope modified Trichrome staining techniques, and EIA. In group 1, parasitological staining techniques and EIA were both positive for Cryptosporidium sp. infection in 3/52 (5.8%) samples and both negative in 45/52 (86.5%) samples, while 4/52 (7.7%) samples were positive in EIA and negative in parasitological staining techniques. Concerning group 2, all samples were negative by EIA and microscopy for Cryptosporidium infection. In conclusion, EIA may be an alternative method for detecting Cryptosporidium-specific coproantigen in HIV/AIDS patients.     

Predicting the impact of a nonsterilizing vaccine against human immunodeficiency virus

Studies of human immunodeficiency virus (HIV) vaccines in animal models suggest that it is difficult to induce complete protection from infection (sterilizing immunity) but that it is possible to reduce the viral load and to slow or prevent disease progression following infection. We have developed an age-structured epidemiological model of the effects of a disease-modifying HIV vaccine that incorporates the intrahost dynamics of infection, a transmission rate and host mortality that depend on the viral load, the possible evolution and transmission of vaccine escape mutant viruses, a finite duration of vaccine protection, and possible changes in sexual behavior. Using this model, we investigated the long-term outcome of a disease-modifying vaccine and utilized uncertainty analysis to quantify the effects of our lack of precise knowledge of various parameters. Our results suggest that the extent of viral load reduction in vaccinated infected individuals (compared to unvaccinated individuals) is the key predictor of vaccine efficacy. Reductions in viral load of about 1 log(10) copies ml(-1) would be sufficient to significantly reduce HIV-associated mortality in the first 20 years after the introduction of vaccination. Changes in sexual risk behavior also had a strong impact on the epidemic outcome. The impact of vaccination is dependent on the population in which it is used, with disease-modifying vaccines predicted to have the most impact in areas of low prevalence and rapid epidemic growth. Surprisingly, the extent to which vaccination alters disease progression, the rate of generation of escape mutants, and the transmission of escape mutants are predicted to have only a weak impact on the epidemic outcome over the first 25 years after the introduction of a vaccine.     

Persistent infection of chimpanzees with human T-lymphotropic virus type III/lymphadenopathy-associated virus: a potential model for acquired immunodeficiency syndrome.

The lymphadenopathy-associated virus (LAV) prototype strain of human T-lymphotropic virus type III/LAV was transmitted to juvenile chimpanzees with no prior immunostimulation by (i) intravenous injection of autologous cells infected in vitro, (ii) intravenous injection of cell-free virus, and (iii) transfusion from a previously infected chimpanzee. All five animals that received more than one 50% tissue culture infective dose were persistently infected with LAV or chimpanzee-passaged LAV for up to 18 months. During this time they developed no illnesses, but they exhibited various degrees of inguinal and axillary lymphadenopathy and significant reductions in rates of weight gain. Detailed blood chemistry and hematologic evaluations revealed no consistent abnormalities, with the exception of immunoglobulin G (IgG) hypergammaglobulinemia, which became apparent in one animal 6 months postinfection and continued at more than 1 year postinfection. Transient depressions followed by increases in the numbers of T4 cells to levels greater than normal were observed in all animals after virus inoculation. However, the number of LAV-infected peripheral blood cells decreased with time after infection. Results of enzyme immunoassays showed that all infected animals seroconverted to IgG anti-LAV within 1 month postinfection and that antibody titers remained high throughout the period of observation. In contrast, only three of the five LAV-infected chimpanzees had detectable IgM antibody responses, and these preceded IgG-specific serum antibodies by 1 to 2 weeks. Virus morphologically and serologically identical to LAV was isolated from peripheral blood mononuclear cells of all infected animals at all times tested and from bone marrow cells taken from one animal 8 months after infection. One chimpanzee that was exposed to LAV only by sharing a cage with an infected chimpanzee developed lymphadenopathy and an IgM response to LAV, both of which were transient; however, no persistent IgG antibody response to LAV developed, and no virus was recovered from peripheral blood cells during a year of follow-up. Thus, LAV readily infected chimpanzees following intravenous inoculation and persisted for extended periods despite the presence of high titers of antiviral antibodies. However, the virus was not easily transmitted from infected to uninfected chimpanzees during daily cage contact.