PACTG P1059

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来源获得了主要资金，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。PACTG 1059是一项I期研究，将评估HIV-1重组疫苗在年轻人中的安全性和耐受性。与老年人相比，HIV-1感染的儿童和青年人胸腺功能相对保留，对新抗原的反应能力提高。因此，18-24岁的年龄组是评价安全性和为HIV感染儿童、青少年和成人的未来研究提供信息的合理人群。一旦在该组中确定了安全性，将考虑进行进一步研究，以评估在其他患者人群中的安全性，并进一步评价免疫原性。最终，这些候选疫苗具有用作预防性和治疗性疫苗的潜力。如果当前研究的结果支持这些产品在该患者人群中的安全性，则将计划在儿童、青少年和年轻人中开展进一步研究，以评估其作为治疗性疫苗的潜力。 受试者将接受两对匹配的重组HIV-1疫苗，这些疫苗采用改良的安卡拉牛痘（MVA）载体和鸡痘载体（FPV）（Therion Biologics Corp.）。每个载体对含有相同的HIV-1插入片段，一个由env/gag组成，另一个由修饰的达特/rev/nef-RT组成，来源于垂直传播的儿科原发分离株（C58 A1，进化枝B）。 Therion使用的HIV-1序列是在马萨诸塞州大学医学中心通过PCR扩增来自外周血单核细胞的前病毒DNA从垂直HIV-1感染的婴儿中分离的，并被命名为HIV-1毒株C58 A1（亚型B，初级分离株）。疫苗表达的env基因含有gp 41的免疫显性部分。修饰达特、rev、nef和逆转录酶（RT）基因以使蛋白质无功能。在反式激活系统中测试了突变的达特蛋白，并且不能激活HIV-1长末端重复序列（LTR）的转录。在逆转录病毒RT活性的比色免疫测定中测试nef-RT融合基因;未检测到酶活性。将这些基因插入两个MVA和两个FPV载体中，每对载体中的一个含有env和gag，另一个含有达特、rev和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.