Timing of establishment of the HIV latent reservoir in subtype C infected women

 描述(申请人提供)：需要终生治疗，以维持对艾滋病毒感染的控制，以及为TENS提供抗逆转录病毒治疗(ART)的全球可持续性 数百万需要治疗的人的安全是一个主要问题。这种情况的唯一替代方案是制定一种能够从人体内根除艾滋病毒的战略。在最近的案例研究中，一些人要么在停止治疗后有效地控制了艾滋病毒的复制，要么完全消灭了病毒。这些发现突出了实现艾滋病毒持久治愈的潜力，并在该领域引起了极大的兴趣。治愈艾滋病毒的障碍是消除潜在的病毒蓄积物。仍然需要完全了解该水库何时建立以及影响其大小和稳定性的因素，特别是在疾病负担最重的撒哈拉以南非洲人口中。在这一应用中，我们建议分析作为时间函数的潜伏病毒的组成，将告知我们病毒何时被沉积在该病毒中，以及它的可能的衰减率。该项目将调查20名感染C亚型病毒的南非妇女，她们是在急性感染中招募的，感染三年后开始接受抗逆转录病毒治疗，此后成功抑制艾滋病毒复制至少四年。我们将比较完整的全长前病毒基因组的数量，以衡量治疗开始后两年和四年的总潜在储存量，以及它如何随着时间的变化而变化。鉴于这些整合病毒中的许多可能仍处于潜伏状态，我们将通过病毒生长试验将完整的前病毒储存库与具有复制能力的病毒的数量进行比较。我们将使用深度测序方法来定义从急性感染到开始治疗的不断演变的病毒群。我们认为，感染三年期间的遗传进化足以让我们绘制出随着时间的推移对潜伏的前病毒储存库的相对贡献以及 建立储存库的时间。最后，我们将研究急性感染和治疗期间的免疫激活如何影响宿主的病毒成分。这项研究将估计非洲妇女潜在储存库的建立时间、大小和稳定性。我们处于独特的地位，可以通过接触一群接受急性感染监测的年轻女性进行这项研究，并接受长达五年的抗逆转录病毒治疗。将潜在的水库观察扩大到欠发达国家的队列，这些国家的宿主因素、亚型和性别可能与发达国家的不同，这将为开发任何潜在的治愈干预措施提供更普遍的方法。

 DESCRIPTION (provided by applicant): Life-long treatment is needed to maintain control of HIV infection, and the global sustainability of providing anti-retroviral therapy (ART) to the tens of millions of people in need of treatment is a major concern. The only alternative to this scenario is to develop a strategy that can eradicate HIV from the body. In recent case studies, some individuals either effectively controlled HIV replication following withdrawal of treatment, o completely eliminated the virus. These findings have highlighted the potential for achieving a lasting HIV cure and have generated substantial interest within the field. The hurdle to an HIV cure is the elimination of the latent reservoir of virus. A complete understanding of when the reservoir is established, and the factors affecting its size and stability, is still required, espeially in Sub- Saharan African populations where the disease burden is greatest. In this application we propose that analyzing the composition of the latent reservoir, as a function of time, will inform us as to when the virus was deposited in the reservoir, and possibly its rate of decay. This project will investigate 20 subtype C-infected South African women who were recruited in acute infection, initiated on ART after three years of infection, and who thereafter successfully suppressed HIV replication for at least four years. We will compare the number of intact full-length proviral genomes, as a measure of the total potential reservoir, at two and four years post treatment-initiation, and how it changes over time. Given that many of these integrated viruses may remain latent, we will compare the intact proviral reservoir to the number of replication competent viruses, as measured by using the viral outgrowth assay. We will use deep sequencing approaches to define the evolving viral swarm, from acute infection to the initiation of treatment. We propose that the genetic evolution during three years of infection is sufficient t allow us to map the relative contribution to the latent proviral reservoir over time as well as the time at which the reservoir was established. Lastly, we will look at how immune activation in acute infection, and during treatment, affects the viral composition of the reservoir. This study will estimate the timing of the establishment, size and stability of the latent reservoir in Africa women. We are uniquely placed to carry out this study through access to a cohort of young women monitored from acute infection, and up to five years on ART. Extending latent reservoir observations to cohorts in less-developed countries where host factors, subtype and gender may differ compared to those in developed countries, will inform the development of a more generalizable approach to any potential cure intervention.