International Studies Of Acquired Immune Deficiency Synd

获得性免疫缺陷综合症的国际研究

• 批准号: 6807922
• 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/6807922
• 关键词: AIDS education /prevention; AIDS therapy; AIDS vaccines; Africa; Brazil; China; HIV infections; India; United States; antiAIDS agent; enzyme linked immunosorbent assay; epidemiology; flow cytometry; helper T lymphocyte; human immunodeficiency virus 1; human immunodeficiency virus 2; human subject; human therapy evaluation; international cooperation; microorganism disease chemotherapy; microorganism immunology; patient oriented research; polymerase chain reaction; sexually transmitted diseases; vaccine development; 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. In collaborative studies we have established cohorts of high-risk individuals in Uganda, Congo, Zambia, Zimbabwe, South Africa, India, China and the U.S. In these cohorts we have characterized the prevalence, incidence, and risk behaviors for HIV infection. In the Rakai district of Uganda we estimated the HIV acquisition rate per coital act among 218 HIV-discordant monogamous couples. The acquisition rate of HIV was 0.0011/act and did not vary significantly by gender, age, pregnancy status, hormonal contraception, reported condom use, or STD diagnosis. Acquisition was significantly associated with current genital ulcer disease in women. No seroconversions occurred among men circumcised at baseline vs. a rate of 0.0013 per act among uncircumcised men. Acquisition increased significantly with higher HIV viral load in the infected partner (0.0001/act < 1700 copies/ml vs. 0.0022/act at > 38,500 copies/ml). HIV acquisition was also associated with HSV-2 seropositivity with an odds ratio of 2.6. In addition, at 5 months post-seroconversion viral load was significantly greater in HSV-2 seropositive compared to HSV-2 seronegative individuals. Thus, HSV-2 infection is associated with HIV acquisition and this interaction of HSV-2 and HIV with subsequent increased viral loads among herpes-positive individuals supports the need for HSV-2 treatment and prophylaxis in infected individuals. Utilizing these Rakai data, we developed a stochastic simulation model to determine the effect of antiretroviral therapy or vaccines in the reduction of HIV incidence in developing countries. Using DHHS treatment guidelines in the model, antiretroviral therapy alone will have a negligible effect on the spread of the epidemic, although it will provide beneficial effects in many other ways for the individual and the population. In contrast, a preventative vaccine, or a therapeutic vaccine that reduces viral load will dramatically reduce HIV transmission and HIV incidence. However, increased risk behaviors would markedly offset these benefits. In order to determine whether the early immunologic and virologic events of HIV infection are unique in a setting with limited access to health care and HIV-1 subtype C infection, we undertook a prospective cohort study to characterize the early natural history of HIV viral load and CD4+ T lymphocyte counts in individuals with recent HIV seroconversion in India. The median viral set-point for Indian seroconverters was 28,729 copies/ml. The median CD4+ T cell count following acute primary infection was 644 cells/ml3. Over the first two years since primary infection, the annual rate of increase in HIV viral load was +8274 RNA copies/ml per year and the annual decline in CD4+ T cell count was ?120 cells/ml3/yr. Although the viral set-point was similar, the median trajectory of increasing viral load in Indian seroconverters was greater than what has been reported in untreated HIV seroconverters in the U.S. These data suggest that the more rapid HIV disease progression described in resource-poor settings may be due to very early virologic and host events following primary HIV infection. In preliminary studies we demonstrated that HIV-1 B/C from the West and A/E from the South are spreading throughout southern China. In studying IDUs in the cities of Pinjxiang and Binyang, the HIV prevalence was 25% and 19% with incident rates of 5.2 and 8.0/100 py, respectively. HIV viral loads were similar by subtype and region. Sequence analysis of the gag-pol region and the C2-V4 env region showed that 93% of the infections in Pinjxiang were A/E while 96% in Binyang were B/C. Greater diversity of the viral sequences was demonstrated in the B/C-infected subjects than those with A/E. Epidemiologic data support different mechanisms for the spread of HIV with multiple introductions of the A/E epidemic into the Pinjxiang and greater spread through sexual transmission, resulting in greater variation in V3. 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传播相关的病毒动力学，并表征世界各地艾滋病毒分子株的传染性和对跨进化枝疫苗的免疫反应。在合作研究中，我们在乌干达、刚果、赞比亚、津巴布韦、南非、印度、中国和美国建立了高危人群队列。在这些队列中，我们描述了艾滋病毒感染的患病率、发病率和危险行为。在乌干达拉凯地区，我们估计了 218 名艾滋病毒不一致的一夫一妻制夫妇每次性交行为的艾滋病毒感染率。 HIV 感染率为 0.0011/行为，并且不会因性别、年龄、怀孕状况、激素避孕、报告的安全套使用或 STD 诊断而显着变化。获得性与女性当前的生殖器溃疡病显着相关。在基线时接受包皮环切的男性中没有发生血清转化，而未接受包皮环切的男性中每次行为的发生率为 0.0013。随着受感染伴侣体内 HIV 病毒载量的增加，获得性显着增加（0.0001/act < 1700 拷贝/ml 对比 0.0022/act > 38,500 拷贝/ml）。 HIV 感染也与 HSV-2 血清阳性相关，比值比为 2.6。此外，在血清转换后 5 个月，HSV-2 血清阳性个体的病毒载量显着高于 HSV-2 血清阴性个体。因此，HSV-2感染与HIV获得有关，并且HSV-2和HIV的这种相互作用以及随后疱疹阳性个体中病毒载量的增加支持了感染个体中对HSV-2治疗和预防的需要。利用这些 Rakai 数据，我们开发了一个随机模拟模型，以确定抗逆转录病毒治疗或疫苗在降低发展中国家艾滋病毒发病率方面的效果。在模型中使用 DHHS 治疗指南，单独抗逆转录病毒治疗对流行病传播的影响可以忽略不计，尽管它会以许多其他方式为个人和人群提供有益的影响。相比之下，预防性疫苗或减少病毒载量的治疗性疫苗将显着减少艾滋病毒传播和艾滋病毒发病率。然而，风险行为的增加将明显抵消这些好处。 为了确定 HIV 感染的早期免疫学和病毒学事件在医疗保健和 HIV-1 C 亚型感染机会有限的环境中是否独特，我们进行了一项前瞻性队列研究，以描述 HIV 病毒载量的早期自然史和印度最近发生 HIV 血清转化的个体的 CD4+ T 淋巴细胞计数。印度血清转化者的中位病毒设定点为 28,729 拷贝/毫升。急性原发感染后的中位 CD4+ T 细胞计数为 644 个细胞/ml3。在初次感染后的头两年中，HIV病毒载量的年增长率为+8274 RNA拷贝/ml每年，CD4+ T细胞计数的年下降率为每年约120个细胞/ml3。尽管病毒设定点相似，但印度血清转化者中病毒载量增加的中位轨迹大于美国未经治疗的艾滋病毒血清转化者中报告的病毒载量增加轨迹。这些数据表明，在资源匮乏的环境中，艾滋病毒疾病进展可能更快。是由于原发性 HIV 感染后非常早期的病毒学和宿主事件所致。 在初步研究中，我们证明来自西方的HIV-1 B/C和来自南方的A/E正在整个中国南方传播。对平吉乡市和宾阳市注射吸毒者的研究显示，艾滋病毒感染率分别为25%和19%，发病率分别为5.2和8.0/100 py。不同亚型和地区的 HIV 病毒载量相似。对gag-pol区和C2-V4 env区的序列分析显示，平吉乡93%的感染属于A/E，宾阳96%的感染属于B/C。与 A/E 感染者相比，B/C 感染者的病毒序列具有更大的多样性。流行病学数据支持不同的HIV传播机制，A/E流行病多次传入平吉乡，并通过性传播进行更大程度的传播，导致V3变异更大。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。