灵长类动物模型在中医药防治艾滋病研究中的应用

动物模型是药物研发和疫苗评价的重要平台,对于抗艾滋病药物和疫苗研究也是不可或缺的。在中医药抗艾滋病研究中,动物模型发挥着重要的作用。但是目前所用动物模型主要为常用的猴免疫缺陷病毒(SIV)感染的猴模型,由于缺少中医特色,对于评价中医药的疗效尚有不足之处。文章简要介绍了灵长类动物艾滋病(AIDS)模型在中医药防治艾滋病研究领域的应用情况,并对目前存在的问题和未来努力的方向进行了探讨。     

The use of nonhuman primate models of HIV infection for the evaluation of antiviral strategies

Several nonhuman primate models are used in HIV/AIDS research. In contrast to natural host models, infection of macaques with virulent simian immunodeficiency virus (SIV) isolates results in a disease (simian AIDS) that closely resembles HIV infection and AIDS. Although there is no perfect animal model, and each of the available models has its limitations, a carefully designed study allows experimental approaches that are not feasible in humans, but that can provide better insights in disease pathogenesis and proof-of-concept of novel intervention strategies. In the early years of the HIV pandemic, nonhuman primate models played a minor role in the development of antiviral strategies. Since then, a better understanding of the disease and the development of better compounds and assays to monitor antiviral effects have increased the usefulness and relevance of these animal models in the preclinical development of HIV vaccines, microbicides, and antiretroviral drugs. Several strategies that were first discovered to have efficacy in nonhuman primate models are now increasingly used in humans. Recent trends include the use of nonhuman primate models to explore strategies that could reduce viral reservoirs and, ultimately, attempt to cure infection. Ongoing comparison of results obtained in nonhuman primate models with those observed in human studies will lead to further validation and improvement of these animal models so they can continue to advance our scientific knowledge and guide clinical trials.     

Treatment of the murine, retrovirus-induced lymphoproliferative immunodeficiency disease (LP-BM5) in C57BL/10 mice with the immunomodulator Imexon.

Imexon (4-imino-1, 3-diazabicyclo-(3.1.0)-hexan-2-one) a cyanoaziridine compound was studied in the treatment of the murine retrovirus-induced immunodeficiency disease model of AIDS (LP-BM5, MAIDS). Imexon, in dose-dependent fashion, partially prevented the development of hypergammaglobulinemia and splenomegaly, and partially prevented the decline in the phytohemagglutinin-induced proliferative response of spleen lymphocytes when started 1 or 15 days after virus inoculation. There was a statistically significant reduction in these disease-associated manifestations. When animals were treated starting 78 or 92 days after virus inoculation, lymphadenopathy was completely abrogated and survival was significantly prolonged in a dose-responsive manner. Since Imexon and other cyanoaziridine compounds have been safely administered to humans, we suggest that this class of compounds be further investigated in both large animal models of HIV infection and in patients with HIV-induced disease.     

Combination of antiretroviral drugs as microbicides

Tenofovir, a highly prescribed drug for the treatment of HIV/AIDS infections, has recently also shown its effectiveness as a potential topical microbicide drug in the prevention of HIV transmission. Here, we discuss the combination of tenofovir with various other antiretrovirals (ARV) highlighting the large class of carbohydrate-binding agents (CBAs) targeting the glycans on the viral envelope gp120 for their anti-HIV activity and their favorable combinatory potential. The tenofovir/CBA and several other ARV combinations consistently showed synergistic antiviral activities. Also combinations of other classes of ARV such as receptor (i.e. CD4, CXCR4 and CCR5) inhibitors, various monoclonal antibodies (mAbs) directed against the HIV envelope gp120 and HIV gp41 inhibitors were demonstrated to have synergistic anti-HIV effects. Moreover, certain antimetabolite drugs that show limited, if any, anti-HIV activity when administered as a single drug, can potentiate the antiviral activity of anti-HIV nucleoside analogues (NRTIs) by creating a beneficial metabolic and/or competitive advantage for the combined NRTIs. Thus, well-defined combinations of ARV may synergize and/or enhance the antiviral potency of the individual drugs and should be envisioned in the design of future microbicide studies. Recently, drugs such as tenofovir and acyclovir were demonstrated to be endowed with a dual (concomitant) antiviral (i.e. anti-HIV/HSV) activity in different in vitro, ex vivo and animal models. They also deserve special attention for their potential to prevent HIV transmission and to concomitantly suppress co-pathogens of HIV such as herpes viruses.     

Dilated cardiomyopathy in retrovirally infected mice

Dilated cardiomyopathy (DCM) is a clinically relevant disease that can occur independently or secondary to other diseases such as HIV infection and AIDS. To study this latter process, we used a model in which mice are infected with the LP-BM5 murine AIDS (MAIDS) retrovirus. Cardiac function of control and infected mice was determined through the in vivo analysis of left ventricular pressure-volume loops. Furthermore, the role of myocarditis was investigated through immunohistochemistry for T-cell, B-cell, and macrophage cardiac infiltrates and Northern blot analysis for tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). End-systolic and end-diastolic volumes were significantly increased and ventricular stiffness was significantly decreased in infected mice, consistent with DCM; however, no staining for inflammatory cellular infiltrates or TNF-α and iNOS was seen. These data support the conclusion that the LP-BM5 HIV model virus causes DCM in the absence of chronic cardiac inflammation. These findings support MAIDS retroviral infection as a new model of idiopathic DCM in which myocarditis does not occur.     

The Th1 to Th2 shift induced by Schistosoma mansoni does not exacerbate murine aids (MAIDS)

Schistosoma mansoni infection in mice is associated with a switch from a Th1 to a Th2-type cytokine response. The role of Th1 and Th2 responses in immune dysregulations associated with AIDS and murine AIDS (MAIDS) is controversial, but a Th2 bias could be associated with disease progression, raising the hypothesis that helminth infections might accelerate the retroviral disease progression. Here, we used the murine model of AIDS to evaluate the course of the viral disease during co-infection with S. mansoni . C57BL/6 mice were infected with S. mansoni cercariae 8 weeks before intravenous challenge with the LP-BM5 retroviral complex. MAIDS did not progress faster in co-infected mice, in terms of spleen and inguinal lymphadenopathy size, ecotropic virus titres in the spleen, or in vitro proliferative responses to mitogen. Th2 cytokine production was not enhanced in co-infected animals, except for an isolated increase in IL-4 production 21 weeks after LP-BM5 infection. Co-infected animals had significantly lower lymph node and spleen weights than mice infected with LP-BM5 only. MAIDS did not influence the granulomatous response to S. mansoni in the liver of co-infected mice. Finally, infection with S. mansoni neither enhanced Th2 cytokine production nor accelerated MAIDS progression in animals subsequently challenged with LP-BM5 .     

The bone marrow in murine AIDS

Summary. In order to increase the understanding of blood cytopenias in HIV infection we have investigated the bone marrow in murine AIDS. C57BL/6 mice infected with the LP-BM5 retrovirus show a decrease in cellularity, numerous haemophagocytic histiocytes, a reduction of all erythroid precursor cells, an increase in eosinophil number and an increase in lymphocytes. Immunostaining with an anti-Pr60^gag antibody shows that the majority of bone marrow cells express the viral protein. Thus, the bone marrow in MAIDS has many similarities with the bone marrow from patients with advanced AIDS and may prove useful as a model for therapy aimed at treating blood cytopenias.     

Immune Dysfunction During Alcohol Consumption and Murine AIDS: The Protective Role of Dehydroepiandrosterone Sulfate

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by the human immunodeficiency virus (HIV) after development of severe immunosuppressive changes. Chronic ethanol (EtOH) consumption accentuates the severity of murine AIDS (MAIDS). Because hormone production is often suppressed by chronic EtOH intake, as well as retrovirus infection, we investigated whether hormone supplementation during chronic EtOH consumption contributes to slowing immune dysfunction caused by LP-BM5 infection and/or EtOH use. Because dehydroepiandrosterone sulfate (DHEAS) was previously shown to have immune-enhancing properties during MAIDS, we determined whether DHEAS reduced cytokine dysregulation otherwise exacerbated by chronic EtOH intake during MAIDS. Adult female C57BL/6 mice were infected with LP-BM5 murine retrovirus. Some were fed 40% EtOH in drinking water and agar gel for 16 weeks postinfection. EtOH consumption further inhibited T- and B-cell proliferation beyond suppression due to retrovirus infection. Interleukin (IL)-2 release produced by concanavalin A-stimulated splenocytes was reduced by EtOH use by infected and uninfected mice. DHEAS overcame much of the effects induced by retrovirus infection and/or EtOH use. IL-4 secretion and IL-6 secretion were enhanced. Hepatic vitamin E levels were decreased by murine retrovirus infection, as well as by EtOH use in both uninfected and infected mice. In addition, DHEAS (0.01%) supplementation during MAIDS prevented the further dysregulation of cytokines and hepatic lipid peroxidation due to EtOH intake, partially restored T- and B-cell proliferation, and maintained hepatic vitamin E levels to near normal levels.     

In vivo evaluation of the anemia induced by azidothymidine (AZT) in a murine model of AIDS

Azidothymidine (AZT) induces severe anemia in patients with acquired immune deficiency syndrome (AIDS). To evaluate the mechanism of anemia in immune-suppressed animals, a murine model of AIDS (MAIDS), caused by infection with LP-BM5 murine leukemia virus (LP-BM5 MuLV) was used at early and late stages of the disease. AZT-induced anemia was dose- and time-dependent. An increased percentage of erythroblasts in bone marrow was observed, with an increased ratio of early to late erythroblasts in both disease stages. Increases in splenic erythroid burst-forming units (BFUe) were observed in early-stage AZT-treated mice. Mean plasma erythropoietin (EPO) levels were increased by AZT in both groups in a dose-dependent manner and were inversely proportional to hematocrit values. These data suggest that the anemia induced by AZT stimulated a response by immature erythroid elements, but that the maturation or survival of early erythroblasts may be impaired.     

西昌市静脉吸毒人群HIV/AIDS流行趋势分析

目的 在西昌市静脉吸毒人群中，利用传播动力学数学模型预测未来几年艾滋病病毒(HIV)伎滋病(AIDS)的流行趋势。方法 对当地静脉吸毒人群进行HIV感染横断面和前瞻性队列研究获得的有关数据，利用离散型HIV／AIDS传播动力学数学模型进行分析。结果 建立了静脉吸毒人群中的HIV／AIDS传播动力学模型，给出了有关参数的确定；通过数值模拟对未来几年HIV感染情况进行了预测。结论 由模型可以看出：如果不采取干预措施，到2010年西昌市静脉吸毒人群中的累计HIV感染者／AIDS患者人数约为1070，HIV感染率约为18％；如果采取适当的干预措施，使得HIV感染者的传染性降低50％，则到2010年累计HIV感染者／AIDS患者人数约为630．HIV感染率约为8％。因此．对吸毒人群施加必要的干预措施．就变成一项非常有意义的工作。     

Coumarins as inhibitors of HIV reverse transcriptase

Acquired immunodeficiency syndrome (AIDS), a degenerative disease of the immune and central nervous systems, is an enormous world-wide health threat. No cure has been found, and research is aimed at developing chemotherapy against the causative agent, human immunodeficiency virus (HIV). Chemotherapy for AIDS has progressed steadily in the past decade. However, new, effective, and less toxic chemotherapeutic agents are still needed. Plants, particularly anti-infective or immunomodulating herbal medicines, can serve as sources of new active leads to be further developed as anti-AIDS drug candidates. A lot of structurally different natural coumarins were found to display potent anti-HIV activity and continued progress is anticipated in the discovery of new leads and in the development of these agents as potential anti-AIDS drug candidates. Recent studies based on the account of various coumarins from plant sources and their analogs--synthetic coumarins, indicate that some of them serve as potent nonnucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The current review demonstrates the variety of coumarins of natural plant origin and synthetic coumarins having unique mechanism of action to one of the most important stage of HIV replication (RT-inhibition). The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed. The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against drug-resistant mutants.     

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.     

Modification of Resistance to Streptococcus pneumoniae by Dietary Ethanol, Immunization, and Murine Retroviral Infection

Hallmarks of the acquired immune deficiency syndrome (AIDS) are immunologic alterations, frequently associated with opportunistic infections. To study such associations, LP-BM5 murine retrovirus infection was used as a murine model of AIDS. Retrovirally infected and uninfected mice were fed a 5% (v/v) ethanol diet for 55 days and then fed a 7% v/v ethanol diet for the final 7 days to assert the role of ethanol as a cofactor in development of murine AIDS. There was a reduction in polymorphonuclear neutrophils count in ethanol-fed groups. Neutrophils increased in retrovirus-infected groups, except those vaccinated 10 days before challenge with live bacteria. The percentage of splenic lymphocytes in the retrovirus-infected group was reduced in comparison with controls. Survival of the mice challenged intraperitoneally with Streptococcus pneumoniae was increased by vaccination and suppressed by dietary alcohol. Retrovirus infection caused a much faster death rate after bacterial challenge than nonretrovirus infected controls. Vaccination played an important role in delaying the death rate in all treated groups. Transferring spleen cells from healthy, unimmunized mice also enabled the retrovirally infected mice to survive the bacterial infection longer. Enhancement of resistance to S. pneumoniae by vaccination and transfer of immunocompetent cells to mice immunosuppressed by retroviral infection show the potential to use immunomodulation to affect disease resistance in AIDS.     

Role of virus replication in a murine model of AIDS-associated interstitial pneumonitis

One of the major complications of HIV infection is the development of interstitial pneumonitis (IP). IP is characterized by lymphocytic infiltration of the lung and may lead to respiratory failure in some cases. The etiology of IP is unknown although it is likely the result of an antiviral or autoimmune response occurring in the lung. To determine the role of viral replication in the development of IP, AZT was evaluated for the ability to inhibit development of lung inflammation in a murine model of retrovirus-associated IP. Mice were infected with LP-BM5 retrovirus, which induces murine AIDS. Infected mice develop IP by 4 weeks postinfection characterized by infiltration of the lung with activated T cells, B cells, and macrophages. Virus could be detected in the lungs of these mice by 2 weeks postinfection and persisted throughout the course of disease. To determine if reduction in viral load affected the disease process, infected mice were treated with AZT for varying periods postinfection and analyzed for the development of IP. Treatment with AZT resulted in a treatment time-dependent reduction of viral RNA in the lungs of infected mice compared to untreated infected mice. The reduction of viral burden in the lungs correlated with a reduction in the severity of IP and decreased production of the proinflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma. These results suggest that continuous viral replication in the lung contributes to the pathogenesis of IP.     

Primary HIV-1 infection: diagnosis and prognostic impact

Acute infection with HIV is symptomatic in approximately two thirds to three-fourths of patients. This stage is defined as primary HIV infection or acute HIV illness. The diagnosis is crucial for public health because counseling can be provided to reduce the risk of transmission and for individual because early antiretroviral treatment could improve the prognosis, slowing the rate of disease progression. Physicians should be aware of the broad clinical spectrum representative of primary HIV infection, which ranges from mild symptoms resembling classic mononucleosis infection to highly severe presentations. Progression to AIDS and to death has been associated with the severity of the acute HIV infection. Clinical trials with combined antiretroviral drugs are needed to identify the best drug combinations as well as the optimal duration of treatment.     

Arterial calcification:animal models

The clinical significance of arterial calcification will continue to grow as the population ages. There is no appropriate animal model required to develop drugs to prevent vascular calcification. Several murine knockout models of some genes have led to new insights into the pathogenesis of arterial calcification. Good animal models can contribute to research progress in this area.     

Effect of cyclophosphamide, total body irradiation, and zidovudine on retrovirus proliferation and disease progression in murine AIDS.

Murine acquired immunodeficiency syndrome (MAIDS) develops when C57B1/6 mice are inoculated with LP-BM5 murine leukemia viruses. Disease progression in these animals is characterized by lymphadenopathy, polyclonal B-cell activation, severe immunodeficiency, and death. Mice with MAIDS have been used to examine the efficacy of antiretroviral therapies for possible use in AIDS patients. In the present work, MAIDS mice were employed to test the hypothesis that established retroviral infection might be cured by the combined use of a cytotoxic agent (cyclophosphamide) and total body irradiation--a regimen reported to have successfully cured HIV-1 infection in one AIDS patient. Results indicate that the ablation of retrovirus-infected lymphoid cells reduced but did not eliminate LP-BM5 infection. Moreover, this regimen was no more effective at controlling virus proliferation or preventing the polyclonal IgG activation characteristic of murine AIDS than was AZT alone.     

Mathematical model of the effect of affinity hemodialysis on the T-cell depletion leading to AIDS

HIV-derived envelope proteins appear to be intimately involved in the destruction of uninfected T cells that leads to AIDS in a process known as the 'bystander effect'. Affinity hemodialysis has been proposed as an effective means of reducing these viral toxins. Using deterministic mathematical models based on the well-known Perelson formulations, the effectiveness of affinity hemodialysis in reducing the levels of viral gp120 was analyzed. Incorporating experimental data on the function of the affinity dialysis system and data from published analyses of HIV viral dynamics, two different models of HIV and AIDS were analyzed. Both models predict a rapid and sustained reduction in gp120 levels. In the model incorporating stem cell dynamics, affinity hemodialysis treatment under several different scenarios was associated with a significant increase in T-cell levels independent of any release from lymphatic tissues. The calculations support the contention that affinity hemodialysis is a potentially useful adjunctive therapy, which can be employed to treat HIV-infected patients in conjunction with drug therapy. For those patients resistant to anti-retroviral drugs or those unable to take the drugs due to the side effects of those medications, affinity hemodialysis treatment may become a viable option.     

社区多资源参与的减少吸毒人群HIV感染危险行为干预模式及效果研究

目的探索社区多资源开展减少吸毒人群艾滋病病毒（HIV）感染危险行为干预模式,评价其效果。方法由卫生医药部门、公安部门、街（村）委和吸毒人群共同参与。干预活动主要是健康教育,免费提供和销售注射器,改变吸毒人群不安全注射行为和性行为。结果建立了社区多资源参与的减少吸毒人群HIV感染危险行为的干预模式。干预后,吸毒人员对艾滋病传播途径和预防知识的知晓率分别提高约35%和23%;吸毒注射次数明显减少,共用针具、共用清洗水和共用容器或棉球比例分别下降了49.93%、46.84%和81.08%。性伴数量减少,性伴有吸毒者的比例下降30%。结论社区多资源参与开展减少吸毒人群HIV感染危险行为干预可行,有效。