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

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）的比例很高，HPV是导致宫颈癌的病毒。通过每半年对参加妇女跨机构艾滋病毒研究（WIHS）的2793名艾滋病毒阳性和975名艾滋病毒阳性妇女进行评估，“WIHS HPV研究”是一个多中心队列，旨在成为艾滋病毒合并感染对HPV和宫颈发育不良影响的权威调查。本申请寻求支持在WIHS中继续进行HPV研究。在新的拨款下必须解决的一个主要人口变化是艾滋病毒阳性人口的老龄化。许多人现在已步入中年。特别是，大量的HIV阳性妇女已经进入更年期。更年期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HPV在围绝经期/绝经后和绝经前感染HIV的妇女中的高患病率。然而，在艾滋病毒阳性妇女中，绝经对HPV自然史/发育不良的影响尚不清楚。此外，除了CD4+ t细胞总数外，HIV+女性中影响HPV的免疫缺陷的性质尚不清楚。最近对WIHS的分析表明，总CD8+ t细胞计数高（而不是低）与HPV/不典型增生有很强的关系。高CD8+激活可能会加速t细胞的衰老/分化，并且据报道会增加功能能力下降的终末分化t细胞的数量。CD4+也有类似的变化。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，我们将按分化阶段量化CD8+和CD4+ t细胞，并研究它们与HPV/不典型增生的关系。CD4+和CD8+ T细胞，以及其他浸润性免疫细胞，也将作为局部免疫反应的一部分来研究不典型增生（即宫颈上皮内瘤变；CIN）。具体来说，我们将使用免疫组织化学对免疫浸润进行为数不多的前瞻性研究之一，以区分(a) CIN-1退化与进展为CIN-2+，以及(b) CIN治疗后复发。最后，我们将在我们最近研究HLA I/II类基因型和宫颈发育不良风险的基础上，通过检查其他信息丰富的免疫基因变异。我们发现，作为KIR（自然杀伤（NK）细胞受体）配体的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- hpv关系的遗传因素，我们现在将研究KIR和IL28B（编码IFN- 3，一种NK细胞激活剂）的多态性。总之，这项资助将有三个目的：首先，研究宫颈HPV/不典型增生自然史与（ia）绝经状态和（ib） CD8+和CD4+ T细胞数量的关系，这些T细胞是幼稚T细胞、中枢记忆T细胞、效应记忆T细胞或终末分化T细胞；二是研究宫颈局部免疫细胞与（iia） CIN-1消退与CIN-2+进展及（iib） CIN治疗后复发的关系；第三，研究KIR和IL28B基因多态性及其与宫颈癌前病变的关系。

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.