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

描述(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是导致宫颈癌的病毒原因。通过对参加妇女机构间艾滋病毒研究(WIHS)的2793名HIV+和975名HIV妇女进行半年一次的评估，WIHS HPV研究旨在成为关于HIV合并感染对HPV和宫颈发育不良影响的权威调查。本申请旨在为WIHS中HPV研究的继续提供支持。在新的赠款下，必须解决的一个重大人口变化是艾滋病毒+人口的老龄化。许多人现在都是中年人。特别是，大量艾滋病毒+妇女经历了更年期。更年期与免疫反应减弱以及宫颈阴道萎缩(削弱上皮屏障)有关。最近的一项研究报告了围绝经期/绝经后与绝经前艾滋病毒妇女中HPV的高流行率。然而，在HIV阳性的妇女中，绝经对HPV自然病史/异常增生的影响尚不清楚。此外，除了CD4+T细胞总数之外，HIV+妇女中影响HPV的免疫缺陷的性质还知之甚少。WIHS最近的分析表明，高(而不是低)的CD8+T细胞总数与HPV/异型增生有很强的相关性。高CD8+激活可能导致T细胞加速老化/分化，并据报道增加功能能力减弱的终末分化T细胞的数量。CD4+也表现出类似的变化。这些免疫细胞中与年龄相关的变化可能是叠加的。我们假设T细胞分化是中年HIV+患者的一个重要因素。在这项资助下，我们将根据分化阶段对CD8+和CD4+T细胞进行量化，并研究它们与HPV/异型增生的关系。此外，还将研究CD4+和CD8+T细胞以及其他浸润性免疫细胞，作为异型增生(即宫颈上皮内瘤变；CIN)局部免疫反应的一部分。具体地说，利用免疫组织化学，我们将对免疫浸润物进行为数不多的前瞻性研究之一，以区分(A)退行性变到CIN-2+的CIN-1，以及(B)治疗后CIN复发。最后，我们将在我们最近对HLAI/II类基因和宫颈发育不良风险的研究的基础上，通过检测其他信息丰富的免疫基因变异来进行研究。我们发现作为KIR(自然杀伤细胞受体)配基的HLA等位基因与致癌性HPV显著相关。为了更好地了解影响NK细胞和HPV关系的遗传因素，我们现在将研究KIR和IL28B(编码NK细胞激活因子)的多态。总而言之，这笔赠款将解决三个目标：第一，研究宫颈HPV/异型增生的自然病史与(Ia)绝经状态的关系，以及(Ib)CD8+和CD4+T细胞的数量是NAOVE T细胞、中央记忆T细胞、效应记忆T细胞或终末分化T细胞的数量；第二，研究局部宫颈免疫细胞与(IIa)CIN-1退化和进展到CIN-2+和(IIB)CIN治疗后复发的关系；第三，研究KIR和IL28B的多态性及其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(HAART)，越来越多具有不同免疫状态的艾滋病毒+妇女现在正在进入宫颈癌发病率达到峰值的年龄段。在HIV+的中年妇女中，了解宫颈疾病和人类乳头瘤病毒(HPV)的生物学风险因素是优先事项。这项应用寻求支持，以继续我们在大规模、长期的HIV+队列中对宫颈HPV/异型增生的研究。计划中的研究将解决与老龄化和免疫功能有关的几个重要问题，这些问题可能会对艾滋病毒阳性妇女的HPV/异型增生的控制产生重大影响：(I)绝经和加速免疫老化(由艾滋病毒引起)对HPV和宫颈异型增生特定类型自然病史的影响；(Ii)局部宫颈免疫浸润，区分宫颈上皮内瘤变(CIN)-1退化到CIN-2+和第二，那些经过治疗但在1年内复发的CIN；(3)影响NK细胞-HPV/异型增生关系的KIR和IL28B基因的多态性。

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.