抗人类免疫缺陷病毒1型广谱中和抗体的研究进展

现行抗反转录病毒治疗药物的联合应用可有效抑制艾滋病进程并显著延长患者寿命,但由于人类免疫缺陷病毒1型(human immunodeficiency virus type 1,HIV-1)潜伏库的存在,艾滋病迄今尚无法治愈。近年发现抗HIV广谱中和抗体能有效降低患者体内病毒载量并延缓疾病进程,为研发艾滋病疫苗和治愈策略带来了曙光,尤其是序贯免疫策略的使用极大推进了广谱中和抗体的开发和应用进程。2018年,美国食品药品管理局(Food and Drug Administration,FDA)批准了第1个临床应用的广谱中性单克隆和抗体,无疑为抗HIV单克隆抗体药物的研发注入了一支强心剂。本文围绕近年来抗HIV广谱中和抗体的研究进展进行综述,探讨未来广谱中和抗体研发面临的挑战。     

Comparison of immunodeficiency and AIDS defining conditions in HIV negative and HIV positive men with haemophilia A.

OBJECTIVE--To investigate the hypothesis that high usage of clotting factor concentrate, rather than HIV infection, is the cause of immunodeficiency and AIDS in men with haemophilia. DESIGN--A comparison of AIDS defining conditions and CD4 counts in HIV positive and HIV negative patients with haemophilia matched for usage of clotting factor concentrate. SETTING--A comprehensive care haemophilia centre. SUBJECTS--17 HIV positive and 17 HIV negative male patients with haemophilia A (age range 12-60 at beginning of study period) who had received similar amounts of clotting factor concentrate yearly over the years 1980-90. MAIN OUTCOME MEASURES--Clinical events listed as AIDS defining in the Centers for Disease Control AIDS definition; CD4 lymphocyte counts; death. RESULTS--Of 108 HIV positive male patients with haemophilia A, only 17 could be matched to an HIV negative patient. This was due to the much higher average usage of factor VIII in the HIV positive group. Between 1980 and 1990, 16 clinical events occurred in nine of the 17 HIV positive patients. No event occurred in the 17 HIV negative patients. In each pair the mean CD4 count during follow up was, on average, 0.5 x 10(9)/l lower in the HIV positive patient. CONCLUSION--These data reject the hypothesis that high usage of clotting factor concentrate, rather than HIV infection, is the cause of immunodeficiency and AIDS in men with haemophilia.     

Evolutionary relationships of the human immunodeficiency viruses

The rapid accumulation of nucleotide sequence data on viral genes has allowed, for the first time, the development of detailed phylogenies of viruses based on an objective criterion. This has been demonstrated clearly in the recent analysis of the evolutionary relationships of HIV - the AIDS virus. When first characterized, HIV seemed aberrant and almost unique in many features. Now it is known to be one of a large group of immunodeficiency viruses, which are widely distributed among primates and other mammals.     

Psychosocial aspects of human immunodeficiency virus infection

Infection with the human immunodeficiency virus (HIV) affects not only the physiological integrity of an individual but their psychological as well. The psychosocial aspects of HIV infection are varied and may be manifested in different behaviors and emotions specific to the stage of infection. These psychosocial aspects of HIV infection are explored using its chronology as a conceptual framework. An overview of issues pertinent to the asymptomatic, acquired immunodeficiency syndrome (AIDS)-related complex and AIDS client is given with suggestions for clinical management.     

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。     

广西人类免疫缺陷病毒感染者/艾滋病患者合并马尔尼菲篮状菌感染的特征及Mp1p抗原快速筛检的研究

为调查广西人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染者/艾滋病(acquired immunodeficiency syndrome,AIDS)患者合并马尔尼菲篮状菌(Talaromyces marneffei,TM)感染的特征并评价TM Mp1p(一种甘露糖蛋白)抗原试剂...     

Inflammatory joint disease and human immunodeficiency virus infection

Nine men positive for antibody to human immunodeficiency virus (HIV) who developed peripheral, non-erosive arthritis were followed up. The clinical features were compatible with reactive arthritis but were atypical in several respects: the joint symptoms were generally severe, persistent, and unresponsive to non-steroidal anti-inflammatory drugs. The onset of arthritis was associated with various infections, none of which are known to be associated with the development of reactive arthritis. HLA typing was performed for three patients, all of whom were positive for HLA-B27. HIV was isolated from the synovial fluid of one patient. No patient had AIDS before developing arthritis, but four progressed to having AIDS after a mean of 7·5 months, and two died. Arthritis resolved in only one patient.The possibility of HIV infection should be considered in all patients with conditions suggesting reactive arthritis. Synovitis in patients with severe immunodeficiency has important pathogenetic implications.     

Molecular pathogenesis of human immunodeficiency virus infection

Molecular studies of the pathogenesis of human immunodeficiency virus (HIV) infections have proceded rapidly following the molecular cloning and nucleotide sequence analysis of the HIV genome. Correlation of biochemical and functional studies of HIV-infected cells with the HIV nucleotide sequence has allowed the identification and preliminary functional characterization of many HIV proteins. These include structural proteins (gag), viral enzymes (pol), and viral regulatory proteins (tat, art). Cloned HIV DNA segments have been utilized as probes for in situ nucleic acid hybridization to study the distribution of HIV-infected cells in acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients. These studies have demonstrated the infection of macrophages as an important component of HIV-induced neurologic disease. Only very low numbers of HIV-infected lymphocytes can be identified in the peripheral blood of infected individuals. Thus, the mechanism of CD4 cell depletion in the pathogenesis of AIDS remain obscure.     

The value of primate models for studying human immunodeficiency virus pathogenesis

Abstract: Research on human immunodeficiency virus (HIV) infection is compromised by the obvious limitation in having for study only virus-infected individuals or those exposed to the virus. Steps involved in transmission or pathogenesis require planned experimentation. The identification of animal models of acquired immunodeficiency syndrome (AIDS) has therefore been helpful for evaluating phases of HIV pathogenesis. Of the seven subgenera of lentiviruses now recognized, two share the characteristics with HIV of a T cell tropism and the associated loss of CD4+ cells in the host associated with disease: the feline immunodeficiency virus (FIV) and the simian immunodeficiency virus (SIV) (Table 1). The other animal lentiviruses grow best in macrophages and their infection generally reflects clinical sequellae of infection of this cell type. This review addresses those features of SIV, HIV, and SHIV infections of non-human primates that illustrate the importance of the animal models of AIDS.     

Thymosin alpha 1: amino acid homology with peptide T from the human immunodeficiency virus envelope

Thymosin alpha 1 has many effects on immune function and its absence in primary immunodeficiency states produce a clinical presentation similar to the one encountered in acquired immune deficiency syndrome (AIDS). Human immunodeficiency virus (HIV), the etiologic agent of AIDS, binds to T4 helper/inducer lymphocytes through specific surface receptors which include the CD4 glycoprotein. Octapeptide T, a component of the HIV envelope, mediates the binding of HIV to its receptor. In this report, we draw attention to the similarity between the amino acid sequence of thymosin alpha 1 and peptide T and its analogues. This similarity can produce a cross-reactivity between thymosin alpha 1 and HIV and may be a factor in the pathophysiology of the acquired immuno-deficiency syndrome.     

The transmission dynamics of human immunodeficiency virus (HIV)

The paper first reviews data on HIV infections and AIDS disease among homosexual men, heterosexuals, intravenous (IV) drug abusers and children born to infected mothers, in both developed and developing countries. We survey such information as is currently available about the distribution of incubation times that elapse between HIV infection and the appearance of AIDS, about the fraction of those infected with HIV who eventually go on to develop AIDS, about time-dependent patterns of infectiousness and about distributions of rates of acquiring new sexual or needle-sharing partners. With this information, models for the transmission dynamics of HIV are developed, beginning with deliberately oversimplified models and progressing--on the basis of the understanding thus gained--to more complex ones. Where possible, estimates of the model's parameters are derived from the epidemiological data, and predictions are compared with observed trends. We also combine these epidemiological models with demographic considerations to assess the effects that heterosexually-transmitted HIV/AIDS may eventually have on rates of population growth, on age profiles and on associated economic and social indicators, in African and other countries. The degree to which sexual or other habits must change to bring the 'basic reproductive rate', R0, of HIV infections below unity is discussed. We conclude by outlining some research needs, both in the refinement and development of models and in the collection of epidemiological data.     

Patterns of primary care of patients infected with human immunodeficiency virus.

To determine the patterns of care of patients infected with the human immunodeficiency virus (HIV), data from 2 sources were analyzed. Initial data obtained from the Washington State HIV/Acquired Immunodeficiency Syndrome (AIDS) Epidemiology Unit indicate that 46% of patients with class IV AIDS were seen by physicians who reported fewer than 5 patients with AIDS, and 68% of all Washington physicians who reported treating patients with AIDS have reported only 1 patient. Subsequent data obtained from a questionnaire distributed in 4 Northwest states suggest that 74% of primary care internists and 73% of family practitioners have some experience in caring for patients with HIV infection, but most of these physicians report fewer than 6 patients in the past 2 years. Although most providers seeing large numbers of HIV-infected patients in their practices were based in the region''s major metropolitan area, 59% of the internists and 55% of the family practitioners surveyed outside of the metropolitan area had seen at least 1 HIV-infected patient in their practices. These results suggest that primary care physicians with relatively little experience treating HIV infection are providing care for a large number of HIV-infected persons. Further study is needed to determine the extent and quality of care provided.     

Transactivation of human immunodeficiency virus promoter by human herpesvirus 6.

Patients with acquired immunodeficiency syndrome (AIDS) are often infected with a number of other heterologous viruses in addition to the initial human immunodeficiency virus (HIV) infection, and these agents could act as potential reactivating agents of latent HIV. A new antigenically distinct herpesvirus, designated human herpesvirus 6 (HHV-6), has recently been isolated from patients with AIDS and has been shown to infect a number of different human cells, specifically human T cells, B cells, and glial cells. Since these are some of the same cells that harbor the AIDS virus, it is quite important to determine any interaction between this new herpesvirus and HIV. In this report, we demonstrate that HHV-6 can trans-activate the HIV promoter in human T-cell lines as measured by the expression of the bacterial gene chloramphenicol acetyltransferase. This indicates that stimulation of HIV gene expression by HHV-6 could play a role in HIV pathogenesis.     

HIVcleave: a web-server for predicting human immunodeficiency virus protease cleavage sites in proteins

According to the 'distorted key theory' [K.C. Chou, Analytical Biochemistry, 233 (1996) 1-14], the information of cleavage sites of proteins by HIV (human immunodeficiency virus) protease is very useful for finding effective inhibitors against HIV, the culprit of AIDS (acquired immunodeficiency syndrome). To meet the increasing need in this regard, a web-server called HIVcleave was established at http://chou.med.harvard.edu/bioinf/HIV/. In this note we provide a step-to-step guide for how to use HIVcleave to identify the cleavage sites of a query protein sequence by HIV-1 and HIV-2 proteases, respectively.     

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.     

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.     

Foreign-protein-mediated immunodeficiency in hemophiliacs with and without HIV

Hemophilia-AIDS has been interpreted in terms of two hypotheses: the foreign-protein-AIDS hypothesis and the Human Immunodeficiency Virus (HIV)-AIDS hypothesis. The foreign-protein-AIDS hypothesis holds that proteins contaminating commercial clotting factor VIII cause immunosuppression. The foreign-protein hypothesis, but not the HIV hypothesis, correctly predicts seven characteristics of hemophilia-AIDS: 1) The increased life span of American hemophiliacs in the two decades before 1987, although 75% became infected by HIV —because factor VIII treatment, begun in the 1960s, extended their lives and simultaneously disseminated harmless HIV. After 1987 the life span of hemophiliacs appears to have decreased again, probably because of widespread treatment with the cytotoxic anti-HIV drug AZT. 2) The distinctly low, 1.3–2%, annual AIDS risk of hemophiliacs, compared to the higher 5–6% annual risk of intravenous drug users and male homosexual aphrodisiac drug users — because transfusion of foreign proteins is less immunosuppressive than recreational drug use. 3) The age bias of hemophilia-AIDS, i.e. that the annual AIDS risk increased 2-fold for each 10-year increase in age —because immunosuppression is a function of the lifetime dose of foreign proteins received from transfusions. 4) The restriction of hemophilia-AIDS to immunodeficiency diseases — because foreign proteins cannot cause non-immunodeficiency AIDS diseases, like Kaposi's sarcoma. 5) The absence of AIDS diseases above their normal background in sexual partners of hemophiliacs — because transfusion-mediated immunotoxicity is not contagious. 6) The occurrence of immunodeficiency in HIV-free hemophiliacs — because foreign proteins, not HIV, suppress their immune system. 7) Stabilization, even regeneration, of immunity of HIV-positive hemophiliacs by long-term treatment with pure factor VIII. This shows that neither HIV nor factor VIII plus HIV are immunosuppressive by themselves. Therefore, AIDS cannot be prevented by elimination of HIV from the blood supply and cannot be rationally treated with genotoxic antiviral drugs, like AZT. Instead, hemophilia-AIDS can be prevented and has even been reverted by treatment with pure factor VIII.     

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...     

Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques

Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P = 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P = 0.7953 and P = 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4(+) T cell depletion, as CD4(+) T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression.