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，导致生殖器疣，上皮内肿瘤和肛门生殖器癌。 HPV相关疾病的诊断和治疗极为昂贵。最近引入的预防性疫苗有可能大大减少由两种类型的宫颈癌（HPV 16和18）的两种类型引起的感染和疾病，以及包括HPV 6和11的四价疫苗，可以防止HPVS 6和11多达90％的生殖器疣。但是，该疫苗的摄取相对较小，尤其是在发展中国家，以及已经被感染的男性和女性的一部分，这意味着数十年来，与HPV相关的疾病将一直是一个重大的公共健康问题。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抗体的血清学测定的发展允许评估HPV感染的患病率，这补充了基于在生殖道标本中检测HPV DNA的主动感染估计值。这些测定的灵敏度有所提高，多路复用方法现在使得测量与数十种HPV类型的抗体以及定义免疫反应性表位的抗体。在AIM 1中，我们将使用多重测定法检查我们现有的年轻男女同龄人的血清中20种HPV类型的流行率，这些年轻男性和男性都有重复的血清学，HPV DNA和性行为指标。 AIM 2的目的是通过采用一种新技术来开发更敏感的血清学测定法，其中通过将抗体抗体与PCR放大的DNA TAG耦合，从而大大增加了抗体的检测。在血清中检测HPV低水平的HPV抗体，口服渗出液和宫颈灌洗将为自然感染的自然史提供新的工具和见解。 AIM 3将检查HPV 16病毒素的表位，即使用一种方法，即使用特定类型的表面暴露环已交换为HPV 31的相应残基的方法。表征抗体反应性差异特别重要。与疫苗接种相比，自然感染诱导。通过了解HPV 16:31交叉反应性的基础，可以更广泛地保护疫苗。 AIM 4提供了一个独特的机会来表征HPV抗体成熟的时间。疫苗接种刺激了大量的NAOVE B细胞，可以使用Solexa测序技术来鉴定，以序列重排的V（D）J免疫球蛋白基因，并结合计算分析。通过接种HPV 6,11、16、16名幼稚的男性并检查其B细胞库，随着时间的流逝，可以鉴定出HPV响应性克隆和躯体超伪装，从而改善抗体结合。综上所述，这些研究将提供有关生殖器HPV感染的普遍性以及对防止HPV感染的基础的新信息。