HIV感染者TMC基因多态、血锌和免疫缺陷水平对HPV持续感染综合效应的队列研究

Persistent infection of Human Papillomavirus (HPV) is the major cause for malignancies including cervical and anal cancer. Most researches focused on HPV infection and cervical cancer in women, while our pilot survey reported that the prevalence of anal HPV infection was 74% among HIV-positive men who have sex with men (MSM), and was 29% among HIV-negative MSM in Zhejiang. The treatment for existing infection is crucial in preventing HPV-related cancers and viral transmission. Host genetic susceptibility, cellular environment for viral life cycle and immune function act together in determining the persistency of infection. However, the mechanism for HPV persistent infection remains unclear. Based on previous studies and literature review, we hypothesize that the immune deficiency caused by HIV infection, plasma zinc level and polymorphisms in several genes are associated with persistent HPV infection. We will set up a prospective cohort and recruit HIV-infected male adults with anal HPV infection. A baseline survey will be conducted and a follow-up visit will be arranged. We will systematically examine the risk of persistent infection, and explore the comprehensive effect of polymorphisms in TMC genes, plasma zinc levels and immune deficiency on persistent infection of HPV among HIV-infected participants. The results will be helpful in controlling the increase of HPV prevalence and in preventing HPV-related cancers.

人乳头瘤病毒(HPV)持续感染是宫颈癌和肛门癌等恶性肿瘤的主要病因。以往研究主要关注女性HPV感染与宫颈癌发生；我们预研究发现浙江HIV阳性男男性行为者肛门HPV感染率74%，HIV阴性者29%。消除已存在的HPV感染是预防相关肿瘤和降低病毒传播的重要手段。HPV持续感染状态可能与宿主遗传易感、病毒生命周期、细胞环境和免疫屏障有关，但其影响因素并不完全清楚。基于前期研究和文献分析，我们假设HIV阳性的HPV感染人群中机体免疫状态、血浆锌水平和若干易感基因多态性分布特征决定了个体的持续感染状态，共同参与HPV感染形成、存在或清除。我们拟通过前瞻性队列研究，以男性HIV感染者为对象，通过基线调查和随访，系统分析男性HIV感染者肛门HPV持续感染特征，和TMC等基因多态性、血锌和免疫缺陷水平对HPV持续感染的综合影响。研究成果将有助于遏制HPV感染人群锐增的形势，有效预防控制HPV感染相关肿瘤。

男性HIV感染者的肛管HPV感染率非常高。本项目建立男性HIV感染者HPV前瞻性随访队列，通过基线调查和随访，系统探索了男性HIV感染者肛管HPV感染、新发、清除和持续感染特征，分析了免疫缺陷水平和遗传易感性对HPV持续感染的综合影响。首先通过基线问卷调查和肛拭子样本检测，获得研究对象流行病学信息和基线HPV感染情况，进而在第12个月左右随访，采集研究对象肛拭子样本并检测，获得肛管HPV新发、清除和持续感染情况。截至结题报告时，85.2%（659/773）研究对象已完成随访。研究人群HPV感染率48.5%，新发感染率16.3例/百人年，持续感染率53.1%。感染率最高的三种致癌亚型为HPV16、52和58。通过多因素logistic回归分析发现近期CD4细胞计数与HPV持续感染有关联，较高的CD4是HPV持续感染的保护因素。通过GWAS全基因组芯片检测基因位点多态性，分析发现rs11046048、rs9494145、rs6920211等SNPs与HPV持续感染关联最密切。综合上述结果，本研究为探讨HPV感染自然史、持续感染状态和识别高危人群奠定了坚实基础，为精准制定防控HPV感染及其相关肿瘤的策略和措施奠定科学依据。项目资助发表SCI英文论文1篇，投稿中1篇，国际合作发表论文1篇；投稿中中文论文2篇。培养在读硕士生1名。项目投入经费21万元，支出19.8万元，各项支出基本与预算相符。剩余经费1.2万元，剩余经费计划用于项目后续支出。