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

描述(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(每1,000人年死亡3人)，并与感染人乳头瘤病毒(HPV)有关。这两个假设是：1)在HIV感染妇女中，HPV的发病率、流行率、持久性和病毒类型的数量都会增加，这些妇女具有不受控制的HIV复制，低水平的CD4计数，以及由于抗逆转录病毒治疗(ART)延迟而持续的免疫功能障碍。我们有一个独特的机会，在海地的一个随机队列中研究抗逆转录病毒治疗对宫颈HPV感染自然历史的影响。2005至2009年间，CD4T细胞计数在200-350个/mm3的HIV感染患者被随机分为两组：立即开始抗逆转录病毒治疗，或推迟抗逆转录病毒治疗，直到他们的CD4T细胞计数降至200个/mm3以下或发展为艾滋病。这项试验表明，早期抗逆转录病毒治疗降低了75%的死亡率(p=.001)。试验中的所有患者都开始接受抗逆转录病毒治疗，并继续接受随访。这一队列中的女性接受了年度巴氏试验的筛查，宫颈样本被冷冻。我们将研究这个队列和储存的宫颈样本，并比较两个研究组之间的HPV发病率、患病率、持久性和多样性。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见解，并可能支持HIV感染女性的早期ART。2)HIV感染增加宫颈细胞中炎症分子前列腺素E2(PGE2)的合成。PGE2是肿瘤发生的重要介质，水平升高可能会影响HPV癌蛋白的产生和发生宫颈癌的风险。我们已经证明PGE2促进HPV病毒癌蛋白E6和E7在宫颈癌细胞中的表达。反过来，E6和E7上调COX-2酶的表达，COX-2是合成PGE2的重要酶，这意味着一个正反馈循环，可以通过药物抑制来降低癌症风险。HIV-1感染还与几种细胞类型中COX-2和PGE2水平的增加有关，尽管对宫颈的影响尚不清楚。我们建议评估参与PGE2合成、分解代谢和信号转导的基因在来自HIV感染和未感染妇女的宫颈细胞中的表达。这些结果将为HIV对PGE2生物学的影响提供新的见解，并可能为未来使用阿司匹林或COX-2抑制剂等阻止PGE2形成的药物进行化学预防试验提供一个机械平台。 公共卫生相关性：宫颈癌是海地艾滋病毒感染妇女癌症死亡的最常见原因(每1000人中有3人死亡)，并与人类乳头瘤病毒(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混合感染对前列腺素E2的影响，前列腺素E2是癌症发生的重要介质。减少前列腺素E2合成的药物(例如阿司匹林)可以作为艾滋病毒感染妇女的癌症防治剂。

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.