Dissecting the influence of HIV infection and treatment with antiretroviral therapy on Human Papillomavirus infection, disease and immunity - Identifying possible targets for therapeutic intervention

人乳头瘤病毒（HPV）相关宫颈癌在HIV阳性妇女中的增加表明HPV特异性CD4 T细胞反应缺陷在发病机制中起重要作用。因此，可以假设，在HIV感染后，甚至在开始高活性抗逆转录病毒治疗（HAART）后，HPV特异性T细胞和抗体反应的耗竭和功能障碍有助于频繁的HPV再感染，增加高风险（HR） HPV类型的多样性和持久性，最终导致恶性细胞转化。我们假设，由选定的抗原靶点组成的治疗性HPV疫苗可以特异性地启动和重建HPV特异性适应性免疫，以防止HAART治疗的HIV+个体的HPV疾病进展。该研究旨在阐明在HAART时代HIV、免疫系统和HPV诱导的癌变之间复杂的相互作用，HPV抗原区域经常被HPV特异性T细胞反应识别，将在免疫功能正常的女性中进行定位，并将为针对HIV+受试者中最常见的HR HPV类型量身定制疫苗的基本原理设计提供基础。在后期阶段，一项将寻求额外伦理批准的副研究计划探索TFDA*批准的亚单位疫苗（Gardasil™）或基于HPV16肽的疫苗（ISA Pharmaceuticals）在接受HAART治疗的健康HIV+女性中的安全性和免疫原性

The increase in Human Papilloma Virus (HPV) associated cervical cancer in HIV+ women implies that defects in the HPV-specific CD4 T cell response play an important role in pathogenesis. It can thus be hypothesized that depletion and dysfunction of HPV-specific T cell and antibody responses after HIV infection and even after initiation of highly active antiretroviral therapy (HAART) contribute to frequent HPV reinfection, increased diversity and persistence of High Risk (HR) HPV types finally leading to malignant cell transformation. We postulate that a therapeutic HPV vaccine consisting of selected antigenic targets can specifically prime and reconstitute HPV-specific adaptive immunity to prevent HPV disease progression in HIV+ individuals on HAART. The proposed study aims to elucidate the complicated interplay between HIV, the immune system and HPV induced carcinogenesis in the era of HAART, HPV antigenic regions frequently recognized by the HPV-specific T cell response will be mapped in immunocompetent women and will provide the basis for rationale design of a vaccine tailored for the HR HPV types most frequently occurring in HIV+ subjects. During a later stage, a side study, which will seek additional ethical approval, is planned to explore the safety and immunogenicity of a TFDA* approved subunit vaccine (Gardasil™) or a HPV16 peptide-based vaccine (ISA Pharmaceuticals) in healthy HIV+ women on HAART