HPV Capsid Antibodies

HPV 衣壳抗体

• 批准号: 8616329
• 负责人: DENISE A. GALLOWAY
• 金额: $ 39.59万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616329
• 关键词: Address; Affinity; Amino Acids; Anogenital cancer; Anogenital venereal warts; Antibodies; Antibody Affinity; Antibody Formation; B cell repertoire; B-Lymphocytes; Binding; Biological Assay; Blood; Capsid; Cervical; Chimera organism; Collection; Complement; Computing Methodologies; Coupled; Coupling; DNA; Detection; Development; Diagnosis; Disease; Dose; Engineering; Epitopes; Exudate; Gardasil; Genital Human Papilloma Virus Infection; Genital system; Goals; Gold; Human; Human Papillomavirus; Human papilloma virus 31; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 6; Immune response; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Individual; Infection; Intraepithelial Neoplasia; Irrigation; Knowledge; Learning; Malignant neoplasm of cervix uteri; Maps; Measures; Methods; Mutation; Natural History; Nature; Oligonucleotides; Oral; Point Mutation; Population; Positioning Attribute; Prevalence; Process; Proteins; Public Health; Recombinants; Research Personnel; Serologic tests; Serological; Serum; Sex Behavior; Specificity; Specimen; Surface; Surveys; Tadpoles; Technology; Testing; Time; Vaccinated; Vaccination; Vaccines; Virion; Virus Diseases; Woman; antigen challenge; base; cervicovaginal; cohort; cross reactivity; follow-up; improved; innovation; insight; interest; men; neutralizing antibody; neutralizing monoclonal antibodies; new technology; optimism; prevent; prophylactic; public health relevance; rapid technique; response; tool; uptake; young man; young woman

DESCRIPTION (provided by investigator): Human papillomaviruses (HPVs) are the most common sexually transmitted viral infections, resulting in genital warts, intraepithelial neoplasia and anogenital cancers. Diagnosis and treatment of HPV-associated disease is extremely costly. The recent introduction of prophylactic vaccines has the potential to greatly reduce infection and disease caused by the two types responsible for approximately 70 per cent of cervical cancers, HPV 16 and 18, and the quadrivalent vaccine, which also includes HPVs 6 and 11, can prevent up to 90 per cent of genital warts. However, the relatively modest uptake of the vaccine, especially in the developing world, and the very high fraction of men and women who are already infected, means that HPV-associated disease will remain a significant public health problem for decades. Thus, continuing to better understand the natural history of genital HPV infection and the basis for a protective immune response is an important goal. The development of serologic assays to detect HPV antibodies has allowed an assessment of the prevalence of HPV infection, which complemented estimates of active infection made on the basis of detecting HPV DNA in genital tract specimens. The assays have improved in sensitivity, and multiplexing methods now make it possible to measure antibodies to dozens of HPV types, as well as defining immunoreactive epitopes. In aim 1, we will use the multiplex assay to examine the prevalence of 20 HPV types in sera from our existing cohorts of young women and men, for whom there are repeated serological, HPV DNA, and sexual behavior measures. The goal of aim 2 is to develop even more sensitive serologic assays by employing a new technology in which the detection of antibody is greatly increased by coupling the anti-human antibody with a DNA tag that is amplified by PCR. Detection of HPV low levels of HPV antibodies in serum, oral exudates and cervical lavage will provide new tools and insights into the natural history of infection. Aim 3 will examine the epitopes on the HPV 16 virion that elicit antibodies, using an approach in which the type-specific surface exposed loops have been swapped for the corresponding residues of HPV 31. It is of particular importance to characterize the differences in antibody reactivity induced by natural infection compared to vaccination. By understanding the basis of the HPV 16:31 cross-reactivity it may be possible to engineer more broadly protective vaccines. Aim 4 provides a unique opportunity to characterize HPV antibody maturation over time. Vaccination stimulates a large number of naove B cells that can be identified using Solexa sequencing technology to sequence segments of the rearranged V(D)J immunoglobulin genes, coupled with computational analyses. By vaccinating HPV 6,11, 16, 18 naive men and examining their B cell repertoire over time it will be possible to identify HPV-responsive clones and the somatic hypermutation that results to improve antibody binding. Taken together these studies will provide important new information on the prevalence of genital HPV infections and new insights into the basis of protection against HPV infection.

描述（由研究者提供）：人乳头瘤病毒 (HPV) 是最常见的性传播病毒感染，可导致生殖器疣、上皮内瘤变和肛门生殖器癌症。 HPV 相关疾病的诊断和治疗费用极其昂贵。最近推出的预防性疫苗有可能大大减少由导致约 70% 宫颈癌的两种类型 HPV 16 和 18 引起的感染和疾病，而四价疫苗（还包括 HPV 6 和 11）可以预防高达 90% 的尖锐湿疣。然而，疫苗的使用率相对较低，尤其是在发展中国家，而且已经感染的男性和女性比例非常高，这意味着 HPV 相关疾病在几十年内仍将是一个重大的公共卫生问题。因此，继续更好地了解生殖器 HPV 感染的自然史和保护性免疫反应的基础是一个重要目标。检测 HPV 抗体的血清学检测方法的发展使得能够评估 HPV 感染的患病率，这补充了根据检测生殖道标本中的 HPV DNA 做出的活动性感染估计。这些检测的灵敏度有所提高，多重方法现在可以测量数十种 HPV 类型的抗体，并确定免疫反应表位。在目标 1 中，我们将使用多重检测来检查现有年轻女性和男性队列血清中 20 种 HPV 类型的患病率，对他们进行重复的血清学、HPV DNA 和性行为测量。目标 2 的目标是通过采用新技术开发更灵敏的血清学测定，其中通过将抗人抗体与通过 PCR 扩增的 DNA 标签偶联来大大提高抗体的检测。检测血清、口腔分泌物和宫颈灌洗液中 HPV 低水平的 HPV 抗体将为了解感染的自然史提供新的工具和见解。目标 3 将检查 HPV 16 病毒粒子上引发抗体的表位，使用的方法是将类型特异性表面暴露环替换为 HPV 31 的相应残基。表征抗体反应性的差异尤为重要与疫苗接种相比，自然感染引起的。通过了解 HPV 16:31 交叉反应的基础，有可能设计出更广泛的保护性疫苗。目标 4 提供了一个独特的机会来表征 HPV 抗体随时间的成熟情况。疫苗接种会刺激大量幼稚 B 细胞，这些细胞可以使用 Solexa 测序技术对重排的 V(D)J 免疫球蛋白基因片段进行测序，并结合计算分析进行识别。通过给未接种 HPV 6,11,16,18 的男性接种疫苗并随着时间的推移检查他们的 B 细胞库，将有可能识别 HPV 反应性克隆和体细胞超突变，从而改善抗体结合。总而言之，这些研究将为生殖器 HPV 感染的流行提供重要的新信息，并为预防 HPV 感染的基础提供新的见解。