HPV & Cervix Neoplasia in a Large, Long Term HIV + Cohort

HPV病毒

• 批准号: 8012982
• 负责人: HOWARD D STRICKLER
• 金额: $ 87.37万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012982
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Activities of Daily Living; Address; Affect; Aftercare; Aging; Alleles; Atrophic; B-Lymphocytes; Biopsy; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cell Count; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervical dysplasia; Cervix Uteri; Cessation of life; Code; Complement; Data; Dendritic Cells; Development; Disease; Dysplasia; Effector Cell; Elderly; Enrollment; Epithelial; Equipment and supply inventories; Evaluation; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Grant; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Histologic; Human Papillomavirus; Human papilloma virus infection; Immune; Immune response; Immune system; Immunohistochemistry; Infection; Integration Host Factors; Investigation; Lesion; Life; Ligands; Malignant neoplasm of cervix uteri; Memory; Menopausal Status; Menopause; Microdissection; NK Cell Activation; Natural History; Natural Killer Cells; Nature; Neoplasms; Oncogenic; Oral; Outcome; Paraffin Embedding; Patients; Peer Review; Phenotype; Phylogenetic Analysis; Population; Population Control; Postmenopause; Premenopause; Prevalence; Process; Prospective Studies; Public Health; RNA; Recurrence; Regulatory T-Lymphocyte; Reporting; Research; Research Design; Research Personnel; Resources; Risk; Risk Factors; Sampling; Specimen; Staging; Staining method; Stains; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Viral; Virus; Woman; age group; age related; base; cell age; cohort; cytotoxic; granzyme B; high risk; immune function; killer immunoglobulin-like receptor; macrophage; middle age; programs; prospective; public health relevance; receptor

DESCRIPTION (provided by applicant): Women with HIV/AIDS are at high risk for cervical cancer, and have high rates of infection with human papillomavirus (HPV), the viral cause of cervical cancer. Through semiannual evaluations of 2,793 HIV+ and 975 HIV- women enrolled in the Women's Interagency HIV Study (WIHS), a multicenter cohort, the "WIHS HPV Study" is intended to be the authoritative investigation of the effects of HIV coinfection on HPV and cervical dysplasia. This application seeks support for continuation of HPV research in the WIHS. A major demographic change that must be addressed under the new grant is the aging of the HIV+ population. Many are now middle-aged. In particular, a large number of HIV+ women have undergone menopause. Menopause has been associated with diminished immune response, as well as cervicovaginal atrophy (weakening the epithelial barrier). A recent study reported high HPV prevalence in peri-/post- vs pre-menopausal HIV- women. Amongst HIV+ women, however, the impact of menopause on HPV natural history / dysplasia is unknown. Furthermore, beyond total CD4+ T-cell count, the nature of the immune deficits in HIV+ women which effect HPV are poorly understood. Recent analyses in the WIHS have shown that there is a strong relation of high (not low) total CD8+ T-cell count with HPV/dysplasia. High CD8+ activation may cause accelerated T-cell aging / differentiation, and is reported to increase the number of terminally differentiated T-cells with diminished functional capacity. CD4+ show similar changes. Age-related changes in these immune cells may be superimposed. We hypothesize that T- cell differentiation is an important factor in middle-aged HIV+ patients. Under this grant, we will quantify CD8+ and CD4+ T-cells by stage of differentiation, and study their relation with HPV/dysplasia. CD4+ and CD8+ T- cells, as well as other infiltrating immune cells, will additionally be studied as part of the local immune response to dysplasia (i.e., cervical intraepithelial neoplasia; CIN). Specifically, using immunohistochemistry we will conduct one of the few prospective studies of the immune infiltrates that distinguish (a) CIN-1 that regress vs progress to CIN-2+, and (b) CIN recurrence after treatment. Lastly, we will build upon our recent study of HLA class I/II genotype and risk of cervical dysplasia by examining additional informative immune gene variants. We found that HLA alleles which act as ligand for KIR (receptors on natural killer (NK) cells) are significantly related to oncogenic HPV. To better understand the genetic factors that affect the NK cell-HPV relationship, we will now study polymorphisms in KIR and IL28B (which codes for IFN-;3, an NK cell activator). In summary, this grant will address three aims: First, to study the associations of cervical HPV/dysplasia natural history with (ia) menopausal status and (ib) the number of CD8+ and CD4+ T-cells that are naove T-cells, central memory T- cells, effector memory, or terminally differentiated T-cells; Second, to study the relation of local cervical immune cells with (iia) CIN-1 regression vs progression to CIN-2+ and (iib) CIN recurrence after treatment; Third, to study polymorphisms in KIR and IL28B and their relation with cervical precancer. PUBLIC HEALTH RELEVANCE: Women with HIV/AIDS are at high risk for cervical cancer. Through the use of highly active antiretroviral therapy (HAART), an increasing number of HIV+ women with varied immune status are now entering the age groups in which cervical cancer rates reach their peak. Understanding the biologic risk factors for cervical disease and human papillomavirus (HPV), the viral cause of cervical cancer, in middle-aged HIV+ women is a priority. This application seeks support to continue our studies of cervical HPV/dysplasia in a large, long term HIV+ cohort. The planned studies will address several important issues regarding aging and immune function that are likely to have a major impact on the control of HPV/dysplasia in HIV+ women: (i) the effects of menopause and accelerated immune aging (caused by HIV) on the type-specific natural history of HPV and cervical dysplasia; (ii) the local cervical immune infiltrates that distinguish cervical intraepithelial neoplasia (CIN)-1 that regress vs progress to CIN-2+ and, secondly, those CIN that are treated but recur within 1 year; and lastly (iii) the polymorphisms in KIR and IL28B genes (which are involved in natural killer (NK) cell activation) that affect the NK cell - HPV/dysplasia relationship.

描述（由申请人提供）：患有艾滋病毒/艾滋病的妇女患宫颈癌的风险很高，并且感染人乳头瘤病毒（HPV）的比率很高，HPV是宫颈癌的病毒原因。通过对2,793名HIV阳性和975名HIV阴性妇女进行半年一次的评估，参加了妇女机构间HIV研究（WIHS），这是一个多中心队列，“WIHS HPV研究”旨在成为HIV合并感染对HPV和宫颈发育不良影响的权威调查。本申请寻求对WIHS继续进行HPV研究的支持。新赠款必须解决的一个重大人口变化是艾滋病毒阳性人口的老龄化。现在很多人都是中年人。特别是，大量艾滋病毒阳性妇女已经绝经。绝经与免疫反应减弱以及宫颈阴道萎缩（上皮屏障减弱）有关。最近的一项研究报告了绝经后/绝经后与绝经前艾滋病毒感染妇女中HPV的高患病率。然而，在HIV阳性妇女中，绝经对HPV自然史/发育不良的影响尚不清楚。此外，除了CD 4 + T细胞总数之外，人们对艾滋病毒+女性免疫缺陷影响HPV的性质知之甚少。WIHS最近的分析表明，高（而不是低）总CD 8 + T细胞计数与HPV/发育不良有很强的相关性。高CD 8+活化可能导致加速的T细胞老化/分化，并且据报道增加了具有降低的功能能力的终末分化T细胞的数量。CD 4+也有类似的变化。这些免疫细胞中的免疫相关变化可能是叠加的。我们假设T细胞分化是中年HIV阳性患者的一个重要因素。根据这项资助，我们将通过分化阶段量化CD 8+和CD 4 + T细胞，并研究它们与HPV/发育不良的关系。CD 4+和CD 8 + T细胞以及其他浸润性免疫细胞将作为对发育异常的局部免疫应答的一部分进行额外研究（即，宫颈上皮内瘤变; CIN）。具体而言，我们将使用免疫组织化学进行为数不多的免疫浸润的前瞻性研究之一，以区分（a）CIN-1消退与进展为CIN-2+，和（B）治疗后CIN复发。最后，我们将在最近对HLA I/II类基因型和宫颈发育不良风险的研究的基础上，通过检查其他信息丰富的免疫基因变体。我们发现作为KIR（自然杀伤（NK）细胞上的受体）配体的HLA等位基因与致癌HPV显著相关。为了更好地了解影响NK细胞-HPV关系的遗传因素，我们现在将研究KIR和IL 28 B（编码IFN-3，一种NK细胞激活剂）的多态性。总之，这项资助将解决三个目标：首先，研究宫颈HPV/发育不良自然史与（ia）绝经状态和（ib）CD 8+和CD 4 + T细胞数量的关系，这些T细胞是原始T细胞、中央记忆T细胞、效应记忆T细胞或终末分化T细胞;第二，研究宫颈局部免疫细胞与（iia）CIN-1消退与进展为CIN-2+和（iib）治疗后CIN复发的关系;第三，研究KIR和IL 28 B基因多态性与宫颈癌前病变的关系。 公共卫生相关性：感染艾滋病毒/艾滋病的妇女患宫颈癌的风险很高。通过使用高效抗逆转录病毒疗法，越来越多的免疫状况不同的艾滋病毒阳性妇女现在进入宫颈癌发病率达到高峰的年龄组。了解宫颈疾病和人乳头瘤病毒（HPV）的生物风险因素，宫颈癌的病毒原因，在中年艾滋病毒阳性妇女是一个优先事项。该申请寻求支持，以继续我们在一个大型长期HIV+队列中对宫颈HPV/发育不良的研究。计划中的研究将解决有关衰老和免疫功能的几个重要问题，这些问题可能对艾滋病毒阳性妇女的HPV/发育不良控制产生重大影响：（由艾滋病毒引起）对HPV和宫颈发育不良的类型特异性自然史;（ii）区分宫颈上皮内瘤变（CIN）-1的局部宫颈免疫浸润，所述CIN-1消退与进展为CIN-2+，其次，那些接受治疗但在1年内复发的CIN;以及最后（iii）影响NK细胞- HPV/发育异常关系的KIR和IL 28 B基因（其参与自然杀伤（NK）细胞活化）的多态性。