PACTG P1059

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。PACTG 1059是一项I期研究，将评估青年人对HIV-1重组疫苗的安全性和耐受性。与老年人相比，感染hiv -1的儿童和年轻人胸腺功能相对保存，对新抗原的反应能力增强。因此，18-24岁年龄组是评估安全性的合理人群，并为今后对感染艾滋病毒的儿童、青少年和成人进行研究提供信息。一旦在该组中确定安全性，将考虑进一步的研究来评估其他患者群体的安全性，并可以进一步评估免疫原性。最终，这些候选疫苗有可能成为有用的预防和治疗疫苗。如果目前的研究结果支持这些产品在该患者群体中的安全性，将计划进一步研究以评估作为治疗性疫苗在儿童、青少年和年轻人中的潜力。受试者将接受两对匹配的重组HIV-1疫苗，使用改良的安卡拉痘苗（MVA）载体和禽痘载体（FPV） （Therion Biologics Corp.）。每个载体对包含相同的HIV-1插入物，一个由env/gag组成，另一个由改良的tat/rev/nef-RT组成，来自垂直传播的儿科初级分离物（C58A1，进化支B）。Therion利用的HIV-1序列是在马萨诸塞大学医学中心通过外周血单核细胞原病毒DNA的PCR扩增从一名垂直感染HIV-1的婴儿中分离出来的，并被命名为HIV-1菌株C58A1 （B亚型，原分离物）。疫苗表达的env基因含有gp41的免疫优势部分。对tat、rev、nef和逆转录酶（RT）基因进行修饰，使蛋白质失去功能。突变的蛋白在反激活系统中进行了测试，无法激活HIV-1-长末端重复序列（LTR）的转录。用比色免疫法检测nef-RT融合基因的逆转录病毒RT活性；未检测到酶活性。这些基因被插入到两个MVA和两个FPV载体中，每一对含有env和gag，另一对含有tat、rev和一个nef-RT融合基因。

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. PACTG 1059 is a phase I study which will evaluate the safety and tolerance of HIV-1 recombinant vaccines in young adults. Children and young adults with HIV-1infection have been shown to have relative preservation of thymic function with improved ability to respond to new antigens as compared to older adults. Therefore, the age group of 18-24 years is a reasonable population to evaluate safety and to inform future studies for HIV infected children, adolescents and adults. Once safety is established in this group, further studies will be considered to assess safety in other patient populations and immunogenicity can be further evaluated. Ultimately, these candidate vaccines have potential to be useful as prophylactic and therapeutic vaccines. If the results of the present studies support safety of these products in this patient population, further studies to evaluate potential as therapeutic vaccines will be planned in children, adolescents and young adults. Subjects will receive two pairs of matching recombinant HIV-1 vaccines that utilize a modified vaccinia Ankara (MVA) vector and a fowlpox vector (FPV) (Therion Biologics Corp.). Each vector pair contains identical HIV-1 inserts, one consisting of env/gag and the other of modified tat/rev/nef-RT, derived from a vertically transmitted pediatric primary isolate (C58A1, clade B). The HIV-1 sequences utilized by Therion were isolated at the University of Massachusetts Medical Center from a vertically HIV-1-infected infant by PCR amplification of proviral DNA derived from peripheral blood mononuclear cells, and were designated as HIV-1 strain C58A1 (subtype B, primary isolate). The env gene expressed by the vaccines contains the immunodominant portion of gp41. The tat, rev, nef and reverse transcriptase (RT) genes were modified in order to render the proteins non-functional. The mutated tat protein was tested in a transactivation system and was unable to activate the transcription of HIV-1- long terminal repeat (LTR). The nef-RT fusion gene was tested in a colorimetric immunoassay for retroviral RT activity; no enzymatic activity was detected. These genes were inserted into two MVA and two FPV vectors, one of each pair containing env and gag, and the other containing tat, rev, and a nef-RT fusion gene.