INFANT RHESUS MACAQUE MODEL FOR SIV VACCINES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。世界卫生组织估计，每年有59万儿童感染艾滋病毒。虽然高效抗逆转录病毒疗法在短期内降低了艾滋病毒感染的发病率和死亡率，但世界上许多地方仍然无法获得这种疗法，而且这种疗法不能治愈疾病。因此，迫切需要艾滋病毒疫苗，发展中国家感染艾滋病毒的妇女所生的母乳喂养婴儿是疫苗开发的关键目标群体。从HIV免疫生物学研究中获得的见解表明，有效的HIV疫苗需要诱导强烈的CD 8 + T细胞应答、CD 4 + T细胞应答和中和抗体。然而，幼儿的免疫系统是不成熟的，如对细菌和病毒感染的易感性增加、对某些疫苗无应答以及T细胞功能缺陷所证明的。因此，为成人设计的艾滋病毒疫苗需要进行测试，并可能进行修改，以使其在新生儿中安全有效。恒河猴婴儿的免疫系统与人类婴儿相似。已利用幼猴研究在人类婴儿中诱导保护性抗体应答的疫苗的使用。完善的SIV/恒河猴模型为HIV/SIV的免疫生物学提供了重要的见解，并且越来越多的试剂和方法可用于详细的免疫学分析。这项研究的目标是与俄勒冈州国家灵长类动物研究中心的疫苗和基因治疗研究所合作，开发一种免疫学上复杂的模型来研究恒河猴的T细胞和B细胞免疫，然后将其用作人类婴儿HIV疫苗开发的动物模型。具体目标是：1）通过比较新生猴与免疫学成熟的幼年猴在用表达SIV gag pol的修饰的安卡拉牛痘病毒（MVA）接种后的抗原特异性CD 8+和CD 4 + T细胞应答，确定幼年恒河猴是否缺乏产生抗原特异性T和B细胞免疫的能力。用重组SIV包膜蛋白疫苗接种后的MVA-SIV 239 gagpol）和抗原特异性CD 4 + T细胞应答和抗体滴度（SIVmac 239 gp 130）在明矾佐剂中;和2）为了确定该MVA/通过比较重组gp 130疫苗接种在恒河猴幼猴中的保护性低于给予SIVmac 251粘膜病毒攻击的幼年猴，病毒复制的程度，在挑战的婴儿与幼年动物和频率和克里思的猴艾滋病的发展，在挑战的婴儿与幼年动物。迄今为止，已完成了两组幼龄动物的研究。在实验动物中，在第二次免疫时（第6周）在两只动物中和第二次免疫后3周（第9周）在所有四只动物中以总CD 8 + T细胞的1/10，000的频率容易地检测到引发的SIV Gag特异性CD 8 + T细胞。在对照动物中，在SIV攻击之前未检测到SIV Gag特异性CD 8 + T细胞。在SIV攻击后，实验动物中T细胞频率增加约10倍，高达总CD 8 + T细胞的1/200，并且在对照动物中变得可检测（范围，1/10，000至1/1000）。有趣的是，使用可溶性四聚体Mamu-A*01/p11 c，CM 9复合物来测量SIV Gag p11 c，CM 9特异性CD 8 + T细胞，我们首先在第9周检测到所有4只动物中超过基线的应答。对新生动物的研究已接近完成。通过四聚体反应测定的疫苗免疫原性在新生儿和青少年中等同。抗体和其他T细胞研究正在进行中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The World Health Organization estimates that 590,000 children acquire HIV infection each year. While highly active anti-retroviral therapy (HAART) has reduced the morbidity and mortality of HIV infection in the short term, it remains unavailable to much of the world and is not curative. Therefore, an HIV vaccine is urgently needed and breast-feeding infants born to HIV-infected women in the developing world are critical target cohorts for vaccine development. Insights gained from studies of the immunobiology of HIV suggest that an effective HIV vaccine will need to induce strong CD8+ T cell responses, CD4+ T cell responses, and neutralizing antibodies. However, the immune system of young infants is immature as evidenced by increased susceptibility to bacterial and viral infections, inability to respond to some vaccines, and deficiencies in T cell function. Therefore, an HIV vaccine designed for adults will need to be tested and potentially modified to be safe and effective in neonates. The immune system of infant rhesus monkeys resembles that of human infants. Infant monkeys have been utilized to study the use of vaccines that induce protective antibody responses in human infants. The well-developed SIV/rhesus macaque model has provided important insights into the immunobiology of HIV/SIV and a growing repertoire of reagents and methods have become available for detailed immunological analyses. The goal of this research is to develop, in conjunction with the Vaccine and Gene Therapy Institute at the Oregon National Primate Research Center, an immunologically sophisticated model to study T cell and B cell immunity in rhesus macaques and then use this as an animal model for HIV vaccine development for human infants. The specific aims are: 1) To determine if infant rhesus monkeys are deficient in their capacity to develop antigen-specific T and B cell immunity by comparison of the neonatal monkey to immunologically mature juvenile monkeys with regard to antigen-specific CD8+ and CD4+ T cell responses following vaccination with modified vaccinia virus Ankara (MVA) expressing SIV gag pol (MVA-SIV239 gag pol) and antigen-specific CD4+ T cell responses and antibody titers following vaccination with recombinant SIV Envelope protein (SIVmac239 gp130) in alum adjuvant; and 2) To determine if this MVA/recombinant gp130 vaccination is less protective in infant rhesus monkeys than in juvenile monkeys given a mucosal viral challenge with SIVmac251 by comparison of the degree of viral replication in challenged infants versus juvenile animals and the frequency and tempo of development of simian AIDS in challenged infants versus juvenile animals. To date, the study of the two juvenile groups of animals has been completed. In experimental animals, primed SIV Gag-specific CD8+ T cells were readily detected at frequencies 1/10,000 of total CD8+ T cells at the time of the second immunization (Week 6) in two animals and 3 weeks following the second immunization (Week 9) in all four animals. In control animals, SIV Gag-specific CD8+ T cells were not detected prior to SIV challenge. Following SIV challenge, T cell frequencies increased approximately 10-fold in experimental animals, as high as 1/200 of total CD8+ T cells, and became detectable in control animals (range, 1/10,000 to 1/1000). Interestingly, using soluble tetrameric Mamu-A*01/p11c, CM9 complexes to measure SIV Gag p11c, CM9-specific CD8+ T cells, we first detected responses over baseline in all four animals at Week 9. The study of neonatal animals is nearly completed. Immunogenicity of the vaccine, as measured by tetramer responses, was equivalent in neonates and juveniles. Antibody and additional T cell studies are in progress.