AIDS Animal Models: Cellular Immunology and Immunogenetics

艾滋病动物模型：细胞免疫学和免疫遗传学

• 批准号: 7732676
• 负责人: Bernard Lafont
• 金额: $ 39.73万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732676
• 关键词: AIDS vaccine development; Acquired Immunodeficiency Syndrome; African; Alleles; Animal Model; Animals; Antiviral Agents; Asians; CD4 Positive T Lymphocytes; CD8B1 gene; Cellular Immunity; Cellular Immunology; Cercopithecus pygerythrus; Characteristics; Class; Complex; Control Animal; Development; Disease; Disease Progression; Disease susceptibility; Exhibits; Experimental Models; Family; Family suidae; Frequencies; Gagging; Genetic; Genome; Genotype; HIV; HIV Infections; Haplotypes; Human; Immune; Immune response; Immunogenetics; Immunologic Deficiency Syndromes; Immunologics; Individual; Infection; Kinetics; Lead; Light; Link; MHC Class I Genes; Macaca; Macaca fascicularis; Macaca mulatta; Major Histocompatibility Complex; Modeling; Molecular; Names; Numbers; Pathogenesis; Peptides; Plasma; Play; Population; Primates; Research; Role; SIV; Sus scrofa; Symptoms; T-Lymphocyte; Tail; Time; Vaccines; Viral; Viral Load result; Virus; Virus Replication; cohort; experience; genetic pedigree; nonhuman primate; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; pig genome; response; simian human immunodeficiency virus; tool; viral RNA

Studies in humans and in macaques have demonstrated that CD8+ T cells responses are associated with the initial control of HIV or SIV replication. Specific major histocompatibility complex (MHC) genotypes have been found to be associated with lower viral loads and slower disease progression. However the exact correlates of protection remain unidentified and cellular immune responses required for an effective vaccine need to be defined. Crucial information can be obtained from experimental models of infection such as infection of Asian macaques with SIV or SHIV viruses, but also from studies of natural hosts of SIVs, such as African green monkeys, which exhibit high viral loads but remain disease-free. Comparison of immune responses induced in these natural hosts and in Asian macaques infected with the same SIV strains would shed light on the protective mechanisms used by African primates to resist the development of immunodeficiency. Three macaque species are used to mimic HIV infection in pathogenesis and vaccine studies, namely rhesus macaques (Macaca mulatta), pig-tailed macaques (M. nemestrina) and cynomolgus monkeys (M. fascicularis). Rhesus macaques are currently the principal non-human primate species used for virologic and immunologic studies. Pig-tailed macaques possess particular susceptibility and disease development characteristics that make this species informative for AIDS research. When infected with SIVagm, pig-tailed macaques maintain high plasma viral loads and develop AIDS-like symptoms, whereas rhesus monkeys, challenged with the same virus, control virus replication to undetectable levels and do not develop disease. Macaques infected with SIV develop AIDS-like disease within a variable time frame, similarly to the disease course in HIV-infected humans. In these settings, the variability in pathogenesis development is not related to the amount of virus inoculated, suggesting that host-specific immunologic and genetic factors play a significant role. Specific MHC class I alleles have been associated with slower disease progression and lower viral loads in humans and in macaques (HLA-B*57 in humans, Mamu-A*01 and Mamu-B*17 in rhesus macaques). A similar link between MHC genetic background and disease course has not been established for pig-tailed macaques. Furthermore the organization of MHC class I genes in the African green monkeys remains unknown. We previously analyzed the MHC class I genes in pig-tailed macaques. We identified 19 classical MHC class I alleles and found that MHC-A and MHC-B loci were duplicated at least once in pig-tailed macaques and no MHC-C locus was detected. This first study performed on in a small cohort of individual pig-tailed macaques revealed the existence of three different MHC-A haplotypes. We have expanded our analysis of MHC-A loci present in the genome of pig-tailed macaques to a larger group of animals revealing that the MHC-A region is very complex in this species. Five Mane-A loci were detected including a highly polymorphic Mane-A1 locus and four oligomorphic loci named Mane-A2, -A3, -A4 and -A6 that are orthologues of MHC-A loci detected in rhesus and cynomolgus macaques. The Mane-A2 locus is present at high frequency (90%) in pig-tailed macaques and encodes an oligomorphic family of alleles (Mane-A*06 family) that are expressed at low levels. The Mane-A3 and -A4 loci encode oligomorphic allele families represented by Mane-A*20 and Mane-A*17 in pig-tailed macaques. Interestingly, one allele encoded by the Mane-A3 locus (Mane-A*20) is shared between three macaque species. Additionally, a fifth MHC-A locus, previously undetected in Indian rhesus macaques, was shown to encode an oligomorphic family of alleles (Mane-A*09 family). All oligomorphic Mane-A loci are not always present in the pig-tailed macaque genome and the combination of the 5 Mane-A loci appears to be variable within a population of pig-tailed macaques. Using pedigree analysis we were able to identify six MHC-A configurations carrying a variable number of MHC-A loci (between two to four Mane-A loci). During the course of this study, we have developed molecular tools that are used for MHC typing of pig-tailed macaques. We have also identified CD8+ T cell responses specific for a SIV p27 Gag peptide (HR9 HQAAMQIIR) in several SHIV infected pig-tailed macaques. After inoculation, these animals controlled viral replication and have remained asymptomatic for up to 6 years with undetectable levels of plasma viral RNA. Other similarly inoculated macaques experienced a complete and irreversible elimination of their CD4+ T cells and had to be euthanized within 6 months post infection. We have found that these responses were restricted by the Mane-A*03 allele.

对人类和猕猴的研究表明，CD8+ T 细胞反应与 HIV 或 SIV 复制的初始控制有关。已发现特定的主要组织相容性复合体 (MHC) 基因型与较低的病毒载量和较慢的疾病进展相关。然而，保护作用的确切相关性仍未确定，并且需要确定有效疫苗所需的细胞免疫反应。重要的信息可以从感染实验模型中获得，例如亚洲猕猴感染 SIV 或 SHIV 病毒，也可以从 SIV 自然宿主的研究中获得，例如非洲绿猴，它们表现出高病毒载量，但保持无病状态。对这些自然宿主和感染相同 SIV 毒株的亚洲猕猴诱导的免疫反应进行比较，将有助于揭示非洲灵长类动物抵抗免疫缺陷发展的保护机制。在发病机制和疫苗研究中，三种猕猴被用来模拟艾滋病毒感染，即恒河猴（Macaca mulatta）、猪尾猕猴（M. nemestrina）和食蟹猴（M. fascicularis）。恒河猴是目前用于病毒学和免疫学研究的主要非人类灵长类动物。猪尾猕猴具有特殊的易感性和疾病发展特征，使该物种为艾滋病研究提供了信息。当感染 SIVagm 时，猪尾猕猴会维持较高的血浆病毒载量并出现类似艾滋病的症状，而受到相同病毒攻击的恒河猴则将病毒复制控制在不可检测的水平，并且不会出现疾病。 感染 SIV 的猕猴会在不同的时间范围内发展出类似艾滋病的疾病，与感染艾滋病毒的人类的病程类似。在这些情况下，发病机制发展的变异性与接种的病毒量无关，这表明宿主特异性免疫和遗传因素发挥着重要作用。在人类和猕猴中，特定的 MHC I 类等位基因与较慢的疾病进展和较低的病毒载量有关（人类的 HLA-B*57，恒河猴的 Mamu-A*01 和 Mamu-B*17）。猪尾猕猴的 MHC 遗传背景和疾病过程之间尚未建立类似的联系。此外，非洲绿猴中 MHC I 类基因的组织仍然未知。 我们之前分析了猪尾猕猴的 MHC I 类基因。我们鉴定了 19 个经典 MHC I 类等位基因，发现 MHC-A 和 MHC-B 位点在猪尾猕猴中至少重复一次，并且未检测到 MHC-C 位点。第一项在一小群猪尾猕猴个体中进行的研究揭示了三种不同 MHC-A 单倍型的存在。我们将对猪尾猕猴基因组中 MHC-A 位点的分析扩展到更大的动物群体，揭示该物种的 MHC-A 区域非常复杂。检测到五个 Mane-A 基因座，包括一个高度多态性的 Mane-A1 基因座和四个名为 Mane-A2、-A3、-A4 和 -A6 的寡态基因座，它们是在恒河猴和食蟹猴中检测到的 MHC-A 基因座的直系同源物。 Mane-A2 基因座在猪尾猕猴中出现频率较高 (90%)，并编码低水平表达的寡态等位基因家族（Mane-A*06 家族）。 Mane-A3 和 -A4 位点编码猪尾猕猴中以 Mane-A*20 和 Mane-A*17 为代表的寡态等位基因家族。有趣的是，三种猕猴物种共有一个由 Mane-A3 基因座 (Mane-A*20) 编码的等位基因。此外，之前在印度恒河猴中未检测到的第五个 MHC-A 基因座被证明编码寡态等位基因家族（Mane-A*09 家族）。所有寡态性 Mane-A 基因座并不总是存在于猪尾猕猴基因组中，并且 5 个 Mane-A 基因座的组合在猪尾猕猴群体中似乎是可变的。通过谱系分析，我们能够识别出 6 个 MHC-A 配置，它们携带不同数量的 MHC-A 位点（2 到 4 个 Mane-A 位点）。在这项研究过程中，我们开发了用于猪尾猕猴 MHC 分型的分子工具。我们还在几只感染 SHIV 的猪尾猕猴中鉴定了针对 SIV p27 Gag 肽 (HR9 HQAAMQIIR) 的 CD8+ T 细胞特异性反应。接种后，这些动物控制了病毒复制，并且在长达 6 年的时间内保持无症状，血浆病毒 RNA 水平检测不到。其他接受类似接种的猕猴的 CD4+ T 细胞被完全且不可逆转地消除，并且必须在感染后 6 个月内被安乐死。我们发现这些反应受到 Mane-A*03 等位基因的限制。