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

人类乳头瘤病毒(HPV)相关宫颈癌在HIV阳性妇女中的增加表明HPV特异性的CD4T细胞反应缺陷在发病机制中起着重要作用。因此，可以推测，在HIV感染后，甚至在开始高效抗逆转录病毒治疗(HAART)后，HPV特异性T细胞和抗体反应的耗竭和功能障碍导致HPV频繁再感染，增加高危(HR)HPV类型的多样性和持久性，最终导致恶性细胞转化。我们推测，由选定的抗原靶点组成的治疗性HPV疫苗可以特异性地激发和重建HPV特异性获得性免疫，以防止HAART中HIV+患者的HPV疾病进展。这项拟议的研究旨在阐明HIV、免疫系统和HPV诱导的致癌之间的复杂相互作用在HAART时代，HPV特异性T细胞反应经常识别的HPV抗原区将在免疫能力强的女性中被绘制出来，并将为针对HIV+受试者中最常见的HR HPV类型定制的疫苗的设计提供理论基础。在稍后的阶段，计划进行一项副作用研究，寻求更多的伦理批准，以探索TFDA批准的亚单位疫苗(Gardasil™)或基于HPV16肽的疫苗(ISA PharmPharmticals)在接受HAART治疗的健康艾滋病毒+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