International Studies Of Acquired Immune Deficiency Syndrome (AIDS)

获得性免疫缺陷综合症（艾滋病）的国际研究

基本信息

批准号：
8745288
负责人：
Thomas Quinn
金额：
$ 63.27万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8745288
关键词：
Acquired Immunodeficiency Syndrome Africa Africa South of the Sahara Algorithms Anti-Retroviral Agents Antibody Avidity Area Asia Avidity Behavioral Biological Biological Assay CD14 gene CD4 Lymphocyte Count Cell Density Cellular Immunology Clinical Clinical Trials Cohort Studies Collaborations Country Data Dendritic Cells Developing Countries Disease Disease Progression Eastern Africa Effectiveness Epidemic Epidemiology Event Female Frequencies Functional disorder Genetic Polymorphism Genital system Genomics HIV HIV-1 HPV-High Risk Heterosexuals Human Papillomavirus Human papilloma virus infection Immunoassay Immunologics Incidence Individual Infection Institutes International Intervention Investigation Kinetics Laboratories Latin America Life Liver diseases Male Circumcision Measurable Measurement Mediating Methods Molecular Monitor Pathogenesis Patients Pharmaceutical Preparations Prevalence Prevention Preventive Intervention Race Randomized Clinical Trials Randomized Controlled Trials Reporting Research Resolution Risk Role Sampling Sexual Transmission Source Southern Africa Techniques Testing Time Uganda Vaccines Viral Viral Load result Virus Diseases Women&apos s Group Work base case control cohort deep sequencing follow-up high risk liver function melting men microbicide monocyte novel pandemic disease pol genes prevent pyrosequencing response sex superinfection transmission process

项目摘要

HIV/AIDS is a global pandemic with 34 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the successful results of a randomized clinical trial of circumcision to prevent HIV acquisition. We have also shown that male circumcision also decreases high-risk human papillomavirus (HR-HPV) prevalence. The reduced HR-HPV prevalence by male circumcision is due to decreased incidence and increased clearance. In addition, male circumcision reduced HR-HPV prevalence and the incidence of multiple HR-HPV infections in HIV-positive men. Among female partners of circumcised men in a randomized controlled trial, we found that circumcision also reduced HR-HPV prevalence by 28%, reduced HR-HPV incidence and increased HR-HPV clearance in female partners. The association between HPV infection and HIV seroconversion risk is unclear and the genital cellular immunology has not previously been evaluated. Thus, we conducted a case-control analysis and found that HPV clearance was associated with subsequent HIV seroconversion. HPV infection was associated with increased epidermal dendritic cell density that potentially mediated HIV seroconversion. Accurate methods to estimate HIV incidence are needed to monitor the leading edge of the epidemic, identify groups at high risk of infection, and evaluate the effectiveness of prevention interventions. We previously determined that the BED capture immunoassay (BED-CEIA), the current assay that is used to estimate the number of new infections in the US was associated with multiple sources of misclassification including: viral suppression, AIDS, and race. To overcome these problems, we developed a multi-assay algorithm (MAA) for estimating cross-sectional HIV incidence in a clade B setting that includes the BED-CEIA, an antibody avidity assay, HIV viral load, and CD4 cell count. Using 1,782 samples from 709 individuals in the US infected 0.1 to 8 years and additionally 500 samples from individuals infected 8+ years, we evaluated more than 13,000 possible algorithms to identify a MAA that had a maximum window period (the median time an individual appears recently infected by the testing algorithm). We determined that using the BED-CEIA and the BioRad avidity assay with less stringent cut offs and in combination with CD4 and viral load, we had a MAA with a window period of 159 days (95%CI 134-186) where none of the 970 samples from individuals infected > 5 years appeared recently infected. We compared annual incidence estimated with the MAA to incidence based on HIV seroconversion in three different longitudinal cohorts. In comparison with the HIVNET001 cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI: 0.70%-1.55%), while the incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI: 0.51%-1.71%). We did a similar analysis for HPTN064 and observed similar incidence estimates MAA-0.13% (95% CI: 0.01%-0.76%) and cohort-0.24% (95% CI: 0.07%-0.62%). We also compared incidence in HPTN 061 and found similar incidence cohort-3.0% (95%CI 2.0 4.4%) vs. MAA-3.4% (95%CI 1.8% - 6.2%). We also initiated studies on the utility of cross-sectional incidence assays in sub-Saharan Africa. Using 2193 samples from long term infected subjects from the Partners in Prevention study, we determined that the frequency of misclassification by both the BED-CEIA and BioRad avidity assay was higher in Eastern Africa (where subtypes A & D predominate) compared to Southern Africa (where subtype C is endemic). Further investigation on samples from the Rakai, Uganda, with known infecting subtype, demonstrated that the misclassification by the BED-CEIA and BioRad avidity assay was ten times higher in subtype D than in subtype A infected individuals. These finding demonstrate that cross-sectional incidence estimates can be determined effectively but may be subject to false rates in areas where subtype D predominates. We have expanded our use of ultra-deep pyrosequencing to identify HIV superinfection and describe its effects on the pandemic. As part of this research we identified the first case of a HIV superinfection associated transmission event from a positive individual to his negative partner. We used data generated examining HIV superinfection in Rakai Uganda to validate a high-resolution melting assay for the measurement of HIV diversity. In addition, we established multiple collaborations to expand our work on HIV superinfection to explore its role on HIV transmission in the HPTN 052 and PEPI clinical trials, occurrence in seroconverters from the CAPRISA 004 clinical trial, and in a group of female sex workers in Kampala Uganda. Using a combination of techniques including deep-sequencing we demonstrated that previously transmitted viral strains were preferentially selected during transmission to a new uninfected individual. We are continuing to use these techniques to assist in the identification of transmission linkage as part of the ongoing follow-up to the HPTN 052 trial. We examined the pathophysiology of HIV in patients with impaired liver function. This study found that HIV infected individuals with measurable liver disease had higher levels of soluble CD14, which is a marker for monocyte activation. However, the opposite was true for HIV uninfected individuals with liver disease. We further examined the role of HIV subtype on pathogenesis. This study examined what viral genomic regions influenced the difference between subtypes A and D in terms of pathogenesis. Our work found that polymorphisms in the pol gene influenced rates of disease progression and was associated with differences in replication capacity.

HIV/艾滋病是一种全球流行病，全世界有 3400 万艾滋病毒感染者。该项目的目标是确定发展中国家艾滋病毒感染的独特流行病学、临床、病毒学和免疫学特征，确定与性传播相关的病毒动力学，并描述国际艾滋病毒分子毒株的传染性和进展情况。疾病。我们之前报道了一项包皮环切术预防艾滋病毒感染的随机临床试验的成功结果。我们还发现，男性包皮环切术还可以降低高危人乳头瘤病毒 (HR-HPV) 的患病率。男性包皮环切术降低 HR-HPV 患病率是由于发病率降低和清除率增加。此外，男性包皮环切术降低了 HIV 阳性男性中 HR-HPV 的患病率以及多种 HR-HPV 感染的发生率。在一项随机对照试验中，在接受包皮环切术的男性的女性伴侣中，我们发现包皮环切术还可以将女性伴侣的 HR-HPV 患病率降低 28%，降低 HR-HPV 发病率并提高 HR-HPV 清除率。 HPV 感染与 HIV 血清转化风险之间的关联尚不清楚，并且生殖细胞免疫学此前尚未进行过评估。因此，我们进行了病例对照分析，发现 HPV 清除与随后的 HIV 血清转化相关。 HPV 感染与表皮树突状细胞密度增加有关，可能介导 HIV 血清转化。需要准确的方法来估计艾滋病毒发病率，以监测流行病的前沿，识别感染高危人群，并评估预防干预措施的有效性。我们之前确定，BED 捕获免疫分析 (BED-CEIA)（当前用于估计美国新感染数量的分析）与多种错误分类来源相关，包括：病毒抑制、艾滋病和种族。为了克服这些问题，我们开发了一种多重检测算法 (MAA)，用于估计 B 分支环境中的 HIV 横截面发病率，其中包括 BED-CEIA、抗体亲合力检测、HIV 病毒载量和 CD4 细胞计数。使用来自美国 709 名感染 0.1 至 8 年个体的 1,782 个样本，以及感染 8 年以上个体的 500 个样本，我们评估了超过 13,000 种可能的算法，以识别具有最大窗口期（个体最近出现的中位时间）的 MAA。被测试算法感染）。我们确定，使用 BED-CEIA 和 BioRad 亲合力测定（截止值不太严格）并结合 CD4 和病毒载量，我们获得了窗口期为 159 天 (95% CI 134-186) 的 MAA，其中没有感染时间超过 5 年的个体的 970 个样本似乎是最近被感染的。我们将 MAA 估计的年发病率与三个不同纵向队列中基于 HIV 血清转化的发病率进行了比较。与 HIVNET001 队列研究相比，基于 HIV 血清转化的年发病率为 1.04%（95% CI：0.70%-1.55%），而使用 MAA 获得的发病率估计值基本相同：0.97%（95% CI：0.51%） -1.71%）。我们对 HPTN064 进行了类似的分析，观察到相似的发生率估计 MAA-0.13%（95% CI：0.01%-0.76%）和队列-0.24%（95% CI：0.07%-0.62%）。我们还比较了 HPTN 061 中的发病率，发现相似的发病率队列 - 3.0% (95%CI 2.0 4.4%) 与 MAA-3.4% (95%CI 1.8% - 6.2%)。我们还启动了关于横断面发病率测定在撒哈拉以南非洲地区的效用的研究。使用预防合作伙伴研究中长期感染受试者的 2193 个样本，我们确定，与南部非洲相比，东非（其中 A 和 D 亚型占主导地位）的 BED-CEIA 和 BioRad 亲和力测定错误分类的频率较高（其中 C 亚型是地方性的）。对来自乌干达拉凯（乌干达拉凯）已知感染亚型的样本进行的进一步调查表明，BED-CEIA 和 BioRad 亲和力测定的错误分类在 D 亚型感染个体中比 A 亚型感染个体高十倍。这些发现表明，可以有效地确定横截面发病率估计值，但在 D 亚型占主导地位的地区可能会出现错误率。我们扩大了超深度焦磷酸测序的使用范围，以识别艾滋病毒重复感染并描述其对大流行的影响。作为这项研究的一部分，我们发现了第一例与艾滋病毒重复感染相关的从阳性个体到其阴性伴侣的传播事件。我们使用在乌干达拉凯检查 HIV 重复感染所生成的数据来验证用于测量 HIV 多样性的高分辨率熔解测定。此外，我们还建立了多项合作，以扩大我们在 HIV 重复感染方面的工作，探索其在 HPTN 052 和 PEPI 临床试验中的 HIV 传播中的作用、CAPRISA 004 临床试验中血清转化者中的发生情况以及坎帕拉的一组女性性工作者中的发生情况乌干达。通过使用包括深度测序在内的技术组合，我们证明了先前传播的病毒株在传播给新的未感染个体的过程中被优先选择。作为 HPTN 052 试验持续后续行动的一部分，我们将继续使用这些技术来协助识别传输联系。我们检查了肝功能受损患者的艾滋病毒病理生理学。这项研究发现，患有可测量肝病的 HIV 感染者的可溶性 CD14 水平较高，这是单核细胞激活的标志物。然而，对于未感染艾滋病毒且患有肝病的个体来说，情况恰恰相反。我们进一步研究了 HIV 亚型在发病机制中的作用。这项研究探讨了哪些病毒基因组区域影响了 A 亚型和 D 亚型在发病机制方面的差异。我们的工作发现，pol 基因的多态性影响疾病进展的速度，并与复制能力的差异相关。