International Studies Of AIDS

国际艾滋病研究

• 批准号: 7192839
• 负责人: Thomas Quinn
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/7192839
• 关键词: AIDS; AIDS education /prevention; HIV infections; clinical research; communicable disease transmission; cryopreservation; enzyme linked immunosorbent assay; flow cytometry; genetic strain; host organism interaction; human genetic material tag; human immunodeficiency virus; human subject; international cooperation; interview; microorganism immunology; microorganism interaction; nucleic acid amplification techniques; polymerase chain reaction; population survey; questionnaires; sexually transmitted diseases; vertical transmission; virus load; western blottings

In this project the specific objectives are to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with perinatal and heterosexual transmission, and to characterize the molecular strains of HIV throughout the world for infectiousness and the immunologic response to cross-clade vaccines. We have established population based cohorts in Uganda, Democratic Republic of the Congo, South Africa, India, China and the U.S. In one cohort in Rakai, Uganda, 788 HIV-discordant couples have been identified, of whom 253 (31.1%) have transmitted infection during a 10-year period. In 397 couples the index partner was male (50.4%) and transmission to the female partner occurred in 118 couples (29.7%); in 376 couples the index partner was female (47.7%) and male infection occurred in 120 instances (31.9%). HIV viral load was the most significant determinant of transmission and the risk of transmission increased 2.5-fold for each log10 increment in HIV viral load. Factors that enhanced transmission were younger age, presence of genital ulcer disease, and early or acute HIV infection. Co-infection with HSV-2 increased HIV viral load in dually infected individuals and enhanced HIV susceptibility in the uninfected individual. HIV viral loads were determined for 256 subjects with early (incident) HIV infection and for 1,293 subjects with later (prevalent) HIV infection. HIV viral load was highest in subjects 25 to 29 years old with incident HIV infection but increased with age in subjects with prevalent HIV infection. Viremia was also higher after seroconversion than in latency and increased with more advanced disease. Genital ulcer disease was consistently associated with higher viral loads in subjects with incident and those with prevalent HIV infections, suggesting that treatment of genital ulcer diseases might reduce HIV viremia. To document viral transmission among partners, molecular sequencing of HIV was performed in samples from 419 HIV-infected individuals, including 84 transmission pairs. Of the 84 transmission pairs, 86% were infected by their sexual partner as indicated by sequence matches. For individuals who reported a monogamous relationship, viral sequences matched in 92% compared to non-monogamous relationships where transmission linkage occurred in 68%. HIV subtype data were determined for 168 index HIV-positive persons and the distribution was subtype A (12.5%), D (72.6%), and recombinant A/D (14.9%). Co-receptor tropism was determined in 108 monogamous couples and we found that subtype A samples were all exclusively CCR5-tropic, subtype D samples (24.6%) were dual CCR5/CXCR4-tropic, and the recombinants were 14.3% dually tropic. These findings are consistent with increased expression of CXCR4 tropism in subtype D infections, resulting in more rapid progression and decreased transmission compared to subtype A infections. To better understand the molecular evolution of HIV-1 viral diversity, we performed a comparative molecular analysis of HIV strains collected from persons in Kinshasa, Democratic Republic of Congo. Analysis of 83 specimens revealed that 44 (53%) had concordant subtypes in three regions (subtype A1, G, D, C, and F1 and CRF O1_AE) and one each had subtypes H and J and sub-subtype A2. The remaining 47% of the samples had mosaic genomes comprising multiple subtype combinations. Similar multi-subtype patterns were also observed in 24 specimens collected 15 years earlier in 1985. Given the complexity of HIV-1 viruses circulating in central Africa, efforts should focus on the development of vaccines that can result in cross-clade immunity. In addition, this high frequency of recombinant viruses, multiple infections, or both would suggest that most of these strains represent mosaic genomes. This would further suggest that the HIV epidemic was well established in central Africa by the early 1980s and that recombinant viruses most likely seeded the early global epidemic. In collaborative studies we examined the hypothesis that HIV viral blips represent random biological and statistical variation around mean steady-state HIV-RNA levels slightly below 50 copies/ml. rather than biologically significant elevations in viremia. Viral blips were detected in nine of ten patients and statistical analysis was consistent with random assay variation and random mean viral load below 50 copies/ml. Blips were of short duration (< 3 days) and of low magnitude (79 median, 79 copies/ml.). Blips did not occur in relationship to illness, vaccination, or directly measured antiretroviral drug concentrations. In approximately 1,000 independent cloned sequences for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or after blips. Most blips in this population appear to represent random biological and statistical variation around the mean of HIV-1 levels below 50 copies/ml rather than clinically significant elevations in viremia. The significance of these studies is that they provide important epidemiologic, clinical, virologic, and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.

该项目的具体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，确定与围产期和异性性传播相关的病毒动力学，并描述世界各地艾滋病毒分子毒株的特征用于跨进化枝疫苗的传染性和免疫反应。我们在乌干达、刚果民主共和国、南非、印度、中国和美国建立了以人群为基础的队列。在乌干达拉凯的一个队列中，已确定了 788 对 HIV 不一致的夫妇，其中 253 对 (31.1%) 已经传播10年内感染。在 397 对夫妇中，指标伴侣是男性（50.4%），118 对夫妇（29.7%）传染给女性伴侣；在376对夫妇中，指标伴侣为女性（47.7%），男性感染者为120例（31.9%）。 HIV 病毒载量是传播最重要的决定因素，HIV 病毒载量每增加 log10，传播风险就会增加 2.5 倍。促进传播的因素包括年龄较小、生殖器溃疡病以及早期或急性艾滋病毒感染。 HSV-2 的合并感染增加了双重感染者的 HIV 病毒载量，并增加了未感染者的 HIV 易感性。确定了 256 名早期（偶发）HIV 感染受试者和 1,293 名晚期（流行）HIV 感染受试者的 HIV 病毒载量。 HIV 病毒载量在 25 至 29 岁的 HIV 感染者中最高，但在 HIV 普遍感染者中随着年龄的增长而增加。血清转化后的病毒血症也高于潜伏期，并且随着疾病的进展而增加。生殖器溃疡病始终与发病者和艾滋病毒感染者的较高病毒载量相关，这表明生殖器溃疡病的治疗可能会减少艾滋病毒病毒血症。为了记录伴侣之间的病毒传播情况，我们对 419 名 HIV 感染者的样本进行了 HIV 分子测序，其中包括 84 个传播对。序列匹配表明，在 84 对传播对中，86% 是被其性伴侣感染的。对于报告一夫一妻制关系的个体，病毒序列匹配率为 92%，而非一夫一妻制关系的病毒序列匹配率为 68%。确定了 168 名 HIV 阳性者的 HIV 亚型数据，分布为 A 亚型（12.5%）、D 亚型（72.6%）和重组 A/D 亚型（14.9%）。在 108 对一夫一妻制夫妇中测定了共受体向性，我们发现 A 亚型样本全部都是 CCR5 向性，D 亚型样本 (24.6%) 是 CCR5/CXCR4 双向性，重组体是 14.3% 双向性。这些发现与 D 亚型感染中 CXCR4 向性表达增加一致，与 A 亚型感染相比，导致进展更快，传播减少。为了更好地了解 HIV-1 病毒多样性的分子进化，我们对从刚果民主共和国金沙萨人身上收集的 HIV 毒株进行了比较分子分析。对 83 个样本的分析显示，44 个样本（53%）在三个区域（亚型 A1、G、D、C、F1 和 CRF O1_AE）具有一致的亚型，并且各有一个亚型 H 和 J 以及亚型 A2。其余 47% 的样本具有包含多种亚型组合的嵌合基因组。在 15 年前（1985 年）收集的 24 个样本中也观察到了类似的多亚型模式。鉴于中部非洲传播的 HIV-1 病毒的复杂性，应重点开发可产生跨进化枝免疫的疫苗。此外，这种高频率的重组病毒、多重感染或两者兼而有之，表明这些毒株中的大多数代表了嵌合基因组。这进一步表明艾滋病毒流行于 20 世纪 80 年代初已在非洲中部流行，而重组病毒很可能为早期全球流行病埋下了种子。在合作研究中，我们检验了这样的假设：HIV 病毒 blip 代表了平均稳态 HIV-RNA 水平略低于 50 拷贝/ml 的随机生物学和统计变异。而不是生物学上显着的病毒血症升高。十名患者中有九名检测到病毒信号，统计分析与随机检测变异和随机平均病毒载量低于 50 拷贝/毫升一致。 Blip 持续时间短（< 3 天）且强度低（中位数 79，79 拷贝/毫升）。异常现象的发生与疾病、疫苗接种或直接测量的抗逆转录病毒药物浓度无关。在大约 1,000 个蛋白酶和逆转录酶的独立克隆序列中，在 blip 之前、期间或之后没有发现新的抗性突变。该群体中的大多数现象似乎代表了 HIV-1 水平平均值低于 50 拷贝/毫升的随机生物学和统计变化，而不是临床上显着的病毒血症升高。这些研究的意义在于，它们提供了发展中国家艾滋病毒感染的重要流行病学、临床、病毒学和免疫学知识，可用于监测该流行病的未来趋势，并制定行为和生物干预措施以防止进一步传播。