Immunodeficiency lentiviral infections in natural and non-natural hosts

The host immune system is profoundly affected during the acute phase of progressive immunodeficiency lentiviral infections. Studies of these alterations have been quite restricted in humans because of the limited availability of samples from acutely HIV-infected persons. Therefore, numerous studies have turned attention to nonhuman primate models. Specifically, SIV-infected rhesus macaques (RMs) have been informative for understanding the pathogenesis of HIV infection in humans. Indeed, advantages of the nonhuman primate model include the ability to study the very early events after infection and the ability to retrieve copious amounts of tissues. In addition, nonhuman primates allow for comparative studies between non-natural and natural hosts for SIV, in which SIV infection results in progression, or not, to AIDS, respectively. Although SIV infection of RM is the best model for HIV infection, the immunologic and/or virologic phenomena in SIV-infected RM do not always reflect those seen in HIV-infected humans. Here virologic and immunologic aspects of acute HIV infection of humans and SIV infection of Asian and African nonhuman primates are discussed and compared in relation to how these aspects relate to disease progression.     

Animal models used for the evaluation of antiretroviral therapies

Several animal models for the study of HIV/AIDS have been established and characterized and have been widely used to study the pathogenesis of HIV/AIDS as well as vaccine development. The purpose of this study was to review the literature and identify the animal models most frequently used for the evaluation of drugs, drug combinations, plant extracts and drug-plant combinations. Four of these animal models were evaluated namely the SIV model due to its similarities in pathogenesis of disease to humans, the FIV and the LP-BM5 model due to wide availability and the SCID murine model that combines components of both systems. The pathogenesis of disease in each model, application in the evaluation of drugs, drug combinations and plant extracts as well as the inherent advantages and disadvantages of each model are discussed. The LP-BM5 murine AIDS (MAIDS) model with its in vitro equivalent was identified as the animal model, although not identical to HIV/AIDS, most suitable for the rapid and cost effective initial screening of drugs, drug combinations, plant extracts and drug-plant combinations.     

NIH conference. Development and evaluation of a vaccine for human immunodeficiency virus (HIV) infection

The development of a safe and effective vaccine for infection with human immunodeficiency virus (HIV) is complicated by several unique scientific, logistic, and ethical issues. These issues include a lack of understanding of protective immunity to HIV and disease development, the absence of an adequate and convenient animal model for studying HIV infection, and difficulties in phase III evaluation of candidate vaccines. Because HIV can be transmitted as either a cell-free or cell-associated virus, a protective immune response against HIV infection will likely require both humoral and cell-mediated immunity. A neutralizing antibody against HIV and an antibody involved in antibody-dependent cellular cytotoxicity have been shown in HIV-infected persons, but their precise relation to protection is unclear. Cytotoxic lymphocytes from HIV-infected persons have been shown to lyse target cells expressing HIV or its proteins. Cloned T cells have been developed that manifest HIV-specific, major histocompatibility-complex class I-restricted cytotoxic capabilities that are broadly specific. Thus far, all attempts to protect chimpanzees, currently the only suitable animal model, from HIV infection have failed. Ongoing vaccine studies in humans include phase I trials of recombinant proteins of the HIV envelope in uninfected persons as well as the administration of whole killed virus to persons already infected with HIV. Rapid progress is being made in the development of new animal models for HIV infection. The establishment of alternative animal models, both primate and small animal models, will greatly facilitate the development of a vaccine for HIV infection.     

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。     

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.     

Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (Macaca nemestrina) model

The global impact of HIV/AIDS intensifies the need for a preventive vaccine and nonhuman primate models can help provide critical insights into effective immunity. Pigtail macaques (Macaca nemestrina) are increasingly studied as a nonhuman primate model for AIDS. We compared the virologic and immunologic characteristics of HIV-1, SIV, and SHIV infection of naive pigtail macaques across a series of preclinical HIV vaccine studies. SIVmac251 and SIVmac239 infection of naive pigtail macaques resulted in a gradual decline in peripheral CD4+ T cells in the setting of high levels of viremia, approximating most closely human infection of HIV-1. In contrast, the CXCR4-utilizing SHIVmn229 virus resulted in rapid depletion of CD4+ T cells and minimal generation of humoral or cellular immune responses, similar to that observed with SHIV89.6P infection of rhesus macaques. Infection with the CCR5-utilizing, rhesus macaque passaged, SHIVSF162P3 resulted in some overall CD4+ T cell decline, however, three of eight macaques naturally control SHIVSF162P3 viremia to very low levels in the setting of robust adaptive immunity. Despite attempts at infecting pigtail macaques with HIV-1 strains passaged in juvenile pigtail macaques in vivo or in PBMC isolated from pigtail macaques in vitro, only lower nonsustained levels of viral replication were observed. Our results provide a series of virologic models with which to evaluate potential AIDS vaccines in pigtail macaques.     

Infection of baboon microglia with SIV-HIV recombinant viruses: role of CD4 and chemokine receptors

Microglia constitute the primary cell type infected with HIV in the brain and play a major role in viral persistence in the CNS and in the development of AIDS dementia. Lack of a suitable animal model and limitations in the availability of human tissues hinder most HIV/AIDS studies investigating the neuropathogenesis of AIDS dementia. The aims of this study were to determine whether baboon microglia can be productively infected with SIV-HIV (SHIV) recombinant viruses in vitro and whether they express HIV-1 receptors and coreceptors. Our results show the presence of mRNA for CD4, CCR5, and CXCR4 chemokine receptors on baboon microglial cells. Microglia lacked mRNA for the CCR3 chemokine receptor. We also show productive infection of baboon microglial cells by two SHIV isolates, SHIV-KU and SHIV-89.6P, and blockade of the infection with soluble CD4 protein, CCR5, and CXCR4 monoclonal antibodies. This study demonstrating the feasibility of infecting baboon microglia with SHIV isolates is an important first step in using the baboon as an alternative nonhuman primate model to study HIV neuropathogenesis.     

From mice to macaques--animal models of HIV nervous system disease

Lentiviral diseases of animals have been recognized for over a century, long before HIV was recognized as the cause of AIDS. All lentiviruses cause neurological disease and productive virus replication in the CNS occurs exclusively in cells of macrophage lineage. The ability to molecularly engineer the inoculum virus, to sample the brain at many different time points from acute through terminal infection and to correlate in vivo with in vitro findings are significant advantages of animal models of HIV CNS disease. The lentiviruses can be divided into two pathogenetic groups--those that cause immunosuppression, including the lentiviruses of humans (HIV), non-human primates (SIV), cats (FIV), and cattle (BIV), and those that cause immunoproliferation, including the lentiviruses of horses (EIAV), sheep (OvLV) and goats (CAEV). Despite extensive study, no rodent lentivirus has been identified, prompting development of alternate strategies to study lentiviral pathogenesis using rodents. The immunosuppressive lentiviruses most closely recapitulate the disease manifestations of HIV infection, and both SIV and FIV have contributed significantly to our understanding of how HIV causes both central and peripheral nervous system disease.     

Expression patterns of phenotypic markers on lymphocytes from human immunodeficiency virus type 2-infected baboons

The development of AIDS in HIV-1-infected humans is associated with profound changes in the expression patterns of lymphocyte phenotypic markers associated with increased immune activation and with decreased recall immune responses. In assessing these immunologic changes in an animal model, we characterized the expression patterns of immune activation markers on lymphocyte subsets during the acute, chronic, and end stages of HIV-2 infection in baboons. Using flow cytometry, we identified 21 human-specific monoclonal antibodies that were cross-reactive with baboon lymphocytes; however, expression of only 2 of these markers was altered significantly after HIV-2 infection. We found an increase in baboon class II antigen (as measured by anti-HLA-DR) in the CD4(+) T cell subset within 8 weeks of infection (p = 0.045). Moreover, after 1 year of infection, CD11b was downregulated on CD8(+) T lymphocytes (p = 0.027). This downregulation of CD11b was consistently observed in all of the groups of baboons that were chronically infected with three different HIV-2 isolates. In addition, we found substantial downregulation of the interleukin 2 receptor (CD25) and upregulation of class II antigen on CD8(+) lymphocytes in a baboon with an AIDS-like disease. These and other phenotypic markers of immune activation may facilitate characterization of the immunopathogenesis of AIDS in nonhuman primate animal models.     

Vaccine Development for Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), is a tick-borne emerging zoonosis with a high case-fatality rate. At present, there is no approved SFTS vaccine, although the development of a vaccine would be one of the best strategies for preventing SFTS. This article focused on studies aimed at establishing small animal models of SFTS that are indispensable for evaluating vaccine candidates, developing these vaccine candidates, and establishing more practical animal models for evaluation. Innate immune-deficient mouse models, a hamster model, an immunocompetent ferret model and a cat model have been developed for SFTS. Several vaccine candidates for SFTS have been developed, and their efficacy has been confirmed using these animal models. The candidates consist of live-attenuated virus-based, viral vector-based, or DNA-based vaccines. SFTS vaccines are expected to be used for humans and companion dogs and cats. Hence for practical use, the vaccine candidates should be evaluated for efficacy using not only nonhuman primates but also dogs and cats. There is no practical nonhuman primate model of SFTS; however, the cat model is available to evaluate the efficacy of these candidate SFTS vaccines on domesticated animals.     

HIV Vaccines: Biological and Clinical Considerations

The discovery of an HIV-1 vaccine is a high priority. Recent advances in HIV vaccine development include an improved understanding about virus biology and structure, and the development of quantitative techniques that enable a detailed analysis of vaccine-induced immune responses in humans. The preclinical vaccine pipeline looks healthy, and a common feature of the new vaccine strategies is their ability to attenuate clinical disease rather than prevent HIV infection in nonhuman primates. Human clinical trials to evaluate the safety and immunogenicity of these vaccine candidates and strategies are being actively pursued.     

Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters

The human T-lymphotropic viruses (HTLVs) types 1 and 2 originated independently and are related to distinct lineages of simian T-lymphotropic viruses (STLV-1 and STLV-2, respectively). These facts, along with the finding that HTLV-1 diversity appears to have resulted from multiple cross-species transmissions of STLV-1, suggest that contact between humans and infected nonhuman primates (NHPs) may result in HTLV emergence. We investigated the diversity of HTLV among central Africans reporting contact with NHP blood and body fluids through hunting, butchering, and keeping primate pets. We show that this population is infected with a wide variety of HTLVs, including two previously unknown retroviruses: HTLV-4 is a member of a phylogenetic lineage that is distinct from all known HTLVs and STLVs; HTLV-3 falls within the phylogenetic diversity of STLV-3, a group not previously seen in humans. We also document human infection with multiple STLV-1-like viruses. These results demonstrate greater HTLV diversity than previously recognized and suggest that NHP exposure contributes to HTLV emergence. Our discovery of unique and divergent HTLVs has implications for HTLV diagnosis, blood screening, and potential disease development in infected persons. The findings also indicate that cross-species transmission is not the rate-limiting step in pandemic retrovirus emergence and suggest that it may be possible to predict and prevent disease emergence by surveillance of populations exposed to animal reservoirs and interventions to decrease risk factors, such as primate hunting.     

The use of SIV-infected rhesus monkeys for the preclinical evaluation of AIDS drugs and vaccines.

Macaque monkeys infected with the simian immunodeficiency virus (SIV) can be used for preclinical testing of drugs and vaccines against acquired immunodeficiency syndrome (AIDS) as well as for the study of AIDS pathogenesis. A number of pathogenic SIV strains that have been well characterized molecularly and biologically are available for animal infection studies. Data generated from in vitro drug sensitivity assays have established, for many classes of compounds, a similar degree of antiviral efficacy against both HIV-1 and the SIVs, although some examples of selective inhibitors of HIV-1 now are known. A number of virus and host parameters have been defined that provide suitable biological endpoints for in vivo efficacy studies during acute and chronic infection of macaque monkeys. Vaccine studies in SIV-infected monkeys have provided hope that immune protection against lentiviruses is possible; SIV systems are playing a major role in systematically comparing various vaccine strategies to determine correlates of immunity and the protection required for mucosal versus parenteral routes of infection. Societal pressures and the expanding AIDS epidemic will continue to encourage early testing of experimental drugs and vaccines in human clinical trials, however, as more data validating the SIV system are generated, the utility of the SIV model in preclinical development likely will become apparent. Impetus to evaluate therapies in this model system will increase if the current method of testing in humans does not identify more effective AIDS therapies in the near future.     

Mechanisms of HIV-1 neurotropism

Human immunodeficiency virus type 1 (HIV) infects macrophages and microglia in the CNS and frequently causes neurocognitive impairment. Although antiviral therapy generally reduces the viral load in the CNS and improves HIV-associated neurological dysfunction, most current antiviral drugs have poor CNS penetrance and cannot completely suppress viral replication. Furthermore, drug-resistance mutations can evolve independently in the CNS. Thus, a long-lived viral reservoir persists in macrophages and microglia in the brain despite antiviral therapy. This review discusses mechanisms underlying the neurotropism of HIV, focusing on the role of the HIV envelope glycoproteins and their interactions with CD4 and the chemokine receptors CCR5 and CXCR4. We review data from studies of neurotropic HIV derived from the brains of patients with HIV-associated neurocognitive impairment as well as studies of nonhuman primate models. Understanding mechanisms that underlie HIV neurotropism and neurovirulence is critical for development of therapeutics to inhibit CNS infection and preventing neurological injury in HIV-infected individuals.     

Animal models for acquired immunodeficiency syndrome

Substantial advances have already been made in the understanding of acquired immunodeficiency syndrome (AIDS). The major issues for AIDS research during the next few years must be practical ones: the development of a safe, effective vaccine for individuals not yet infected with the causative virus and the development of drug therapies for those already infected. Suitable animal models will be needed for studies designed to achieve these goals. Areas of investigation in animal models can be divided into four categories on the basis of increasing direct relevance to AIDS in humans: retroviruses that have no obvious, close relation to human immunodeficiency virus (HIV) but can induce chronic diseases with manifestations that include immunologic abnormalities; ungulate lentiviruses; HIV-related viruses of Old World primates; and HIV infection of chimpanzees. It is hoped that important research developments in experimental models can be quickly extrapolated to human AIDS.     

用CRISPR/Cas9系统消除潜伏的HIV前病毒基因组及其感染细胞的研究进展

艾滋病在全球采用联合抗逆转录病毒治疗后发病率及死亡率呈持续下降趋势,使之成为一种可管理的慢性传染病。但因受各种因素制约,艾滋病仍然是全球一个重要公共卫生问题。HIV/AIDS持续存在的主要原因是现有的治疗无法清除人体中存在的HIV潜伏库,由于这种库的存在,HIV/AIDS患者必须终生使用抗病毒药物来抑制病毒复制和反弹。成簇规律间隔短回文重复序列和相关核酸酶Cas9(CRISPR/Cas9)系统几年前以一种简单、快速及易操作的基因编辑技术问世,多项研究表明其在HIV感染的细胞和在动物模型实验中具有消除或破坏HIV储存库或HIV感染细胞的潜力,可能由此产生治愈HIV/AIDS的方法。本文分析了CRISPR/CAS9系统应用于消除潜伏HIV的结果,并对可能产生的问题和趋势进行了讨论。     

Abrogation of attenuated lentivirus-induced protection in rhesus macaques by administration of depo-provera before intravaginal challenge with simian immunodeficiency virus mac239

In nonhuman primate models of acquired immunodeficiency syndrome, live attenuated lentiviruses provide the most reliable protection from systemic and mucosal challenge with pathogenic simian immunodeficiency virus (SIV). Although live attenuated lentiviruses may never be used in humans because of safety concerns, understanding the nature of the protective immune mechanisms induced by live attenuated vaccines in primate models will be useful for developing other vaccine approaches. Approximately 60% of rhesus macaques immunized with nonpathogenic simian-human immunodeficiency virus (SHIV) strain 89.6 are protected from infection or clinical disease after intravaginal (IVAG) challenge with pathogenic SIVmac239. The goal of the present study was to determine whether administration of Depo-Provera before IVAG challenge with SIV decreases the protective efficacy of infection with SHIV89.6. The rate of protection after IVAG challenge with SIVmac239 was significantly lower (P<.05), and the acute postchallenge plasma viral RNA levels were significantly higher (P<.006), in Depo-Provera-treated, SHIV89.6-immunized macaques than in Depo-Provera-naive, SHIV89.6-immunized macaques. In the primate model of sexual transmission of human immunodeficiency virus, treatment with progesterone before IVAG challenge with a pathogenic virus can decrease the efficacy of a model "vaccine."     

Requirements for simian immunodeficiency virus antigen-specific in vitro proliferation of T cells from infected rhesus macaques and sooty mangabeys

The measurement of cell-mediated immunity against the etiologic agent of human AIDS (HIV) in the non-human primate model of AIDS (simian immunodeficiency virus, SIV) has been difficult. In general, culture of peripheral blood mononuclear cells from HIV-1- and SIV-infected humans and monkeys, respectively, with purified inactivated HIV and SIV virus preparations has given inconsistent or negative proliferative responses. However, we describe herein an assay which consists of coculturing monocytes that have been pulsed with inactivated SIVsmm with nylon-wool-purified autologous T cells, leading to antigen-specific T-cell proliferation. The proliferative response, which predominantly occurs in CD4+ T cells, is major histocompatibility complex (MHC) class II-restricted and requires antigen processing. This assay will greatly facilitate the identification of the immunodominant epitopes recognized by T cells in sooty mangabeys, which are naturally infected but remain clinically asymptomatic, and in rhesus macaques, in which experimental infection leads to clinical symptomatology similar to human AIDS, eventually resulting in death.     

CD8(+) T cells in preventing HIV infection and disease

The complex interplay between the host immune response and HIV has been the subject of intense research over the last 25 years. HIV and simian immunodeficiency virus (SIV) CD8 T cells have been of particular interest since they were demonstrated to be temporally associated with reduction in virus load shortly following transmission. Here, we briefly review the phenotypic and functional properties of HIV-specific and SIV-specific CD8 T-cell subsets during HIV infection and consider the influence of viral variation with specific responses that are associated with disease progression or control. The development of an effective HIV/AIDS vaccine combined with existing successful prevention and treatment strategies is essential for preventing new infections. In the context of previous clinical HIV/AIDS vaccine trials, we consider the challenges faced by therapeutic and vaccine strategies designed to elicit effective HIV-specific CD8 T cells.     

IL-15 and HIV infection: lessons for immunotherapy and vaccination

IL-15 is a pleiotropic and multifunctional cytokine that has a diverse array of distinct biological effects in the body. It plays a crucial role in host defense from viral and non-viral intracellular pathogens. The cytokine is essential for the development and differentiation of NK cells and for homeostatic expansion of CD8+ memory T cells, NKT cells and certain subsets of intestinal intra-epithelial lymphocytes (iIEL). It acts as a survival factor and inhibits spontaneous apoptosis in T, B and NK cells by increasing expression of different anti-apoptotic proteins. Several studies have shown that IL-15 production is compromised in HIV-infected AIDS patients and exogenous IL-15 drastically enhances functions of immune cells from these patients. Considering these distinct immune enhancing effects, relative safety in animal models, and minimal effects on HIV replication, IL-15 may represent a better cytokine for immune reconstitution in these patients. Furthermore, IL-15 may also act as a better adjuvant in eliciting antiviral immunity in anti-HIV vaccine strategies.