Natural History and Pathogenesis of HPV/HIV co-infection in Haiti

描述（由申请人提供）：宫颈癌是海地艾滋病毒感染妇女癌症死亡的主要原因（3例死亡/1，000患者年），与人乳头瘤病毒（HPV）感染有因果关系。这两个假设是：1）HPV的发病率、流行率、持续性和病毒类型的数量在HIV感染的女性中增加，这些女性具有不受控制的HIV复制、低最低CD 4计数和由于延迟开始抗逆转录病毒疗法（ART）而导致的持续免疫功能障碍。我们有一个独特的机会来研究ART对海地随机队列宫颈HPV感染自然史的影响。在2005年至2009年期间，CD 4 T细胞计数为200 - 350个细胞/mm 3的HIV感染患者被随机分配立即开始ART或推迟ART，直到他们的CD 4 T细胞计数降至200个细胞/mm 3以下或他们患上艾滋病。这项试验表明，早期ART使死亡率降低了75%（p= 0.001）。试验中的所有患者都开始接受ART治疗，并继续接受随访。该队列中的妇女每年进行一次巴氏试验，并冷冻宫颈样本。我们将研究这一队列和宫颈样本库，并比较两个研究组之间的HPV发病率，患病率，持续性和多样性。这些数据将为HIV免疫功能障碍、ART免疫重建和HPV感染之间的关系提供深入了解，并可能支持HIV感染妇女早期接受ART。2)HIV感染增加宫颈细胞中炎症分子前列腺素E2（PGE 2）的合成。PGE 2是肿瘤发生的重要介质，其水平升高可能影响HPV癌蛋白的产生和发生宫颈癌的风险。我们已经表明，PGE 2促进宫颈癌细胞中HPV病毒癌蛋白E6和E7的表达。反过来，E6和E7上调酶考克斯-2的表达，该酶是PGE 2合成中的重要酶，这表明可以被抑制以降低癌症风险的正反馈环。HIV-1感染也与几种细胞类型中考克斯-2和PGE 2产生水平的增加有关，尽管对子宫颈的影响尚不清楚。我们建议评估从HIV感染和未感染妇女获得的宫颈细胞中参与PGE 2合成、catalysts和信号传导的基因的表达。这些结果将为HIV对PGE 2生物学的影响提供新的见解，并为未来使用阿司匹林或考克斯-2抑制剂等阻断PGE 2形成的药物进行化学预防试验提供机制平台。 公共卫生相关性：子宫颈癌是海地艾滋病毒感染妇女中最常见的癌症死亡原因（每1 000患者年3例死亡），并与人乳头瘤病毒（HPV）感染有因果关系。我们将确定抗逆转录病毒治疗和免疫重建对HIV感染妇女HPV感染自然史的影响，并研究HIV/HPV合并感染对前列腺素E2的影响，前列腺素E2是一种炎症分子，是癌症发展的重要介质。减少前列腺素E2合成的药物（如阿司匹林）可以作为艾滋病毒感染妇女的癌症预防剂。

DESCRIPTION (provided by applicant): Cervical cancer is the leading cause of cancer death in HIV infected women in Haiti, (3 deaths/1,000 patient years), and is causally linked to infection with human papillomavirus (HPV) infection. The two hypotheses are: 1) HPV incidence, prevalence, persistence, and number of viral types are increased in HIV infected women who have uncontrolled HIV replication, low nadir CD4 count, and persistent immune dysfunction due to a delay in initiation of antiretroviral therapy (ART). We have a unique opportunity to study the effects of ART on the natural history of cervical HPV infection in a randomized cohort in Haiti. Between 2005 and 2009, HIV infected patients with a CD4 T cell count of 200 - 350 cells/mm3 were randomized to initiate ART immediately or to defer ART until their CD4 T cell count fell below 200 cells/mm3 or they developed an AIDS illness. This trial showed that early ART decreased mortality by 75% (p=.001). All patients in the trial were initiated on ART and continue to be followed. Women in this cohort were screened with an annual Pap test, and cervical samples were frozen. We will study this cohort and banked cervical samples and compare HPV incidence, prevalence, persistence, and diversity between the two study groups. The data will provide insights into the relationship between HIV immune dysfunction, ART immune reconstitution, and HPV infection and may support earlier ART for HIV infected women. 2) HIV infection increases the synthesis of the inflammatory molecule Prostaglandin E2 (PGE2) in cervical cells. PGE2 is an important mediator of oncogenesis, and increased levels may affect HPV oncoprotein production and the risk of developing cervical cancer. We have shown that PGE2 promotes expression of the HPV viral oncoproteins E6 and E7 in cervical cancer cells. In turn, E6 and E7 up-regulate expression of the enzyme COX-2, which is an important enzyme in the synthesis of PGE2, suggesting a positive feedback loop that can be pharmacologically inhibited to reduce the risk of cancer. HIV-1 infection is also associated with increased levels of COX-2 and PGE2 production in several cell types, although the effects in the cervix are unknown. We propose to evaluate the expression of genes involved in PGE2 synthesis, catabolism, and signaling in cervical cells obtained from HIV infected and uninfected women. Results will provide new insights into the effects of HIV on PGE2 biology and could provide a mechanistic platform for future chemoprevention trials with drugs that block the formation of PGE2 such as aspirin or COX-2 inhibitors. PUBLIC HEALTH RELEVANCE: Cervical cancer is the most common cause of cancer death In HIV infected women in Haiti (3 deaths per 1,000 patient-years) and is causally linked to human papillomavirus (HPV) infection. We will determine the effect of antiretroviral therapy and immune reconstitution on the natural history of HPV infection in HIV infected women, and study the effect of HIV/HPV co-infection on prostaglandin E2, an inflammatory molecule that is an important mediator of cancer development. Drugs that decrease synthesis of prostaglandin E2 (e.g. aspirin) could serve as cancer prevention agents for HIV infected women.