Konya J, Dillner J
Laboratory of Tumor Virus Epidemiology, Microbiology and Tumor Biology Center, Karolinska Institute, S-17177 Stockholm, Sweden.
Adv Cancer Res. 2001;82:205-38. doi: 10.1016/s0065-230x(01)82007-8.
The establishment of human papillomavirus (HPV) infection as a major cause of several human cancer forms, notably cervical cancer, has spurred development of prophylactic and/or therapeutic HPV vaccines for prevention of cervical neoplasia. Knowledge of the immunity to HPV forms the basis for such endeavors.
A literature review of humoral and cellular immunity to HPV. The overview on human leukocyte antigen (HLA) and cervical cancer was expanded to a formal metaanalysis, where relevant articles were located by Medline search and citation analysis and graded by preassigned quality criteria on study design.
The antibody response to the HPV particle is dominated by a neutralizing antibody response to a typespecific, conformationally dependent immunodominant epitope. Vaccines based on viral particles lacking the viral genome (virus-like particles, VLPs) have been highly successful in preventing and treating HPV infection in several animal model systems. In humans, the serum antibody response to VLPs is stable over time, also after the HPV infection has been cleared, resulting in HPV serology being used as a marker of cumulative HPV exposure in spite of the fact that a significant proportion of HPV-exposed subjects fail to seroconvert. More than 90% of HPV infections will clear spontaneously. The factors that determine whether an HPV infection is cleared or persists and increases the risk for cancer are not known, but cellular immunity is implicated. Several HLA class II haplotypes are associated with cervical cancer: DQw3 increases and DR13 decreases the risk for cervical cancer in general (odds ratios (OR) and 95% confidence intervals (CI): 1.25(1.15-1.37) and 0.69 (0.56-0.85), respectively); DR15 increases the risk for HPV16-carrying cancer (OR: 1.47; CI: 1.20-1.81); and DR7 may be either protective or increase the risk. Most cervical cancers have downregulated the expression of at least one HLA class I antigen, whereas class II expression is increased in infected epithelium. A Th2 cytokine profile is associated with progression to cervical cancer. HPV-antigen-specific proliferative responses have been detected in many studies, although it is not entirely clear whether these responses are HPV type specific or may be cross-reactive between HPV types. Specific cytotoxic T lymphocyte (CTL) responses were originally reported in only a minority of infected subjects, typically cancer patients, but with advancing technology, specific CTLs can be stimulated from about half of the women with HPV-carrying disease. In animal model systems, CTL responses can mediate clearance.
The antibody response to HPV is a mediator of type-specific protective immunity, which forms the basis for prophylactic vaccine candidates. The cellular immunity to HPV is implicated as an important factor in cervical carcinogenesis, but the main targets and types of responses that mediate HPV clearance are not established.
人乳头瘤病毒（HPV）感染已被确认为多种人类癌症（尤其是宫颈癌）的主要病因，这推动了预防性和/或治疗性HPV疫苗的研发，以预防宫颈肿瘤形成。对HPV免疫的了解是此类研究的基础。
对HPV的体液免疫和细胞免疫进行文献综述。将关于人类白细胞抗原（HLA）与宫颈癌的概述扩展为正式的荟萃分析，通过Medline检索和引文分析查找相关文章，并根据预先设定的研究设计质量标准进行分级。
对HPV颗粒的抗体反应主要由针对型特异性、构象依赖性免疫显性表位的中和抗体反应主导。基于缺乏病毒基因组的病毒颗粒（病毒样颗粒，VLPs）的疫苗在多个动物模型系统中预防和治疗HPV感染方面非常成功。在人类中，对VLPs的血清抗体反应随时间稳定，即使HPV感染已清除也是如此，这使得HPV血清学被用作累积HPV暴露的标志物，尽管相当一部分暴露于HPV的受试者未能发生血清转化。超过90%的HPV感染会自发清除。决定HPV感染是被清除还是持续存在并增加癌症风险的因素尚不清楚，但细胞免疫与之相关。几种HLA II类单倍型与宫颈癌有关：DQw3一般会增加宫颈癌风险，DR13则会降低宫颈癌风险（优势比（OR）和95%置信区间（CI）分别为：1.25（1.15 - 1.37）和0.69（0.56 - 0.85））；DR15会增加携带HPV16癌症的风险（OR：1.47；CI：1.20 - 1.81）；DR7可能具有保护作用或增加风险。大多数宫颈癌至少下调了一种HLA I类抗原的表达，而II类表达在感染上皮中增加。Th2细胞因子谱与宫颈癌进展相关。在许多研究中都检测到了HPV抗原特异性增殖反应，尽管尚不完全清楚这些反应是否是HPV型特异性的，或者是否可能在HPV型之间发生交叉反应。最初仅在少数感染受试者（通常是癌症患者）中报道了特异性细胞毒性T淋巴细胞（CTL）反应，但随着技术进步，大约一半患有HPV相关疾病的女性可以刺激产生特异性CTL。在动物模型系统中，CTL反应可介导清除。
对HPV的抗体反应是型特异性保护性免疫的介质，这构成了预防性候选疫苗的基础。对HPV的细胞免疫被认为是宫颈致癌过程中的一个重要因素，但介导HPV清除的主要靶点和反应类型尚未明确。
