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

 描述（由申请人提供）：需要终身治疗以保持对艾滋病毒感染的控制，以及向数十人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死亡率是一个主要问题。这种情况的唯一替代方案是制定一项可以从体内根除艾滋病毒的战略。在最近的案例研究中，一些人在停止治疗后有效地控制了艾滋病毒的复制，或者完全消除了病毒。这些发现突出了实现持久治愈艾滋病毒的潜力，并在该领域引起了极大的兴趣。治愈艾滋病的障碍是消除潜伏的病毒库。仍然需要全面了解水库何时建立，以及影响其规模和稳定性的因素，特别是在疾病负担最大的撒哈拉以南非洲人口中。在本申请中，我们提出，分析潜伏水库的组成，作为时间的函数，将告知我们，当病毒沉积在水库，并可能其衰减率。该项目将调查20名感染C亚型的南非妇女，她们在急性感染中被招募，在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。我们将比较治疗开始后2年和4年时完整全长前病毒基因组的数量，作为总潜在储存库的衡量标准，以及它如何随时间变化。考虑到许多这些整合的病毒可能保持潜伏状态，我们将比较完整的前病毒库与复制能力病毒的数量，如通过使用病毒生长试验测量的。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演变中的病毒群。我们认为，在三年的感染过程中的遗传进化足以使我们能够绘制出随着时间的推移对潜伏前病毒库的相对贡献， 水库建成的时间。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水库的病毒组成。这项研究将估计非洲妇女潜在水库的建立时间、规模和稳定性。我们处于独特的地位，通过访问一个队列的年轻女性监测急性感染，并长达五年的ART进行这项研究。扩展潜在水库的观察队列在欠发达国家的主机因素，亚型和性别可能不同于发达国家相比，将通知发展一个更普遍的方法，任何潜在的治愈干预。

 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.