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

C 亚型感染女性中 HIV 潜伏病毒库建立的时机

• 批准号: 8838888
• 负责人: Ronald I Swanstrom
• 金额: $ 35万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838888
• 关键词: Acute; Address; Affect; Africa; Africa South of the Sahara; African; Aftercare; Anti-Retroviral Agents; Berlin; Biological; Biological Assay; CD4 Positive T Lymphocytes; Case Study; Cells; Clinical; Cohort Studies; Collaborations; DNA; Deposition; Developed Countries; Developing Countries; Development; Future; Gender; Genome; HIV; HIV Infections; HIV-1; Individual; Infection; Inflammation; Integration Host Factors; Intervention; Knowledge; Laboratories; Latent Virus; Lead; Length; Life; Maps; Measures; Memory; Monitor; Nature; Patients; Phylogenetic Analysis; Population; Population Study; Prevention; Proviruses; Recruitment Activity; Relative (related person); Rest; Risk; Role; T-Lymphocyte Subsets; Time; Viral; Virus; Withdrawal; Woman; burden of illness; cohort; deep sequencing; env Genes; genetic evolution; genome sequencing; immune activation; inflammatory marker; interest; public health relevance; success; treatment program; viral DNA; young woman

 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.

 描述（由应用提供）：需要终身治疗来维持对艾滋病毒感染的控制，以及向TENS提供抗逆转录病毒疗法（ART）的全球可持续性 数百万需要治疗的人是一个主要问题。这种情况的唯一替代方法是制定一种可以从体内放射性艾滋病毒的策略。在最近的案例研究中，一些人要么有效地控制了治疗后的HIV复制，因此O完全消除了该病毒。这些发现强调了实现持久艾滋病毒治疗的潜力，并在该领域产生了巨大的兴趣。艾滋病毒治愈的障碍是消除病毒的潜在水库。在撒哈拉以南非洲人群中，何时需要完全了解水库何时建立水库以及影响其规模和稳定性的因素。在本应用中，我们建议分析潜在储层的组成，随着时间的流逝，将告知我们何时将病毒沉积在储层中，并可能其衰减率。该项目将调查20种亚型C感染的南非妇女，这些妇女在急性感染中被招募，在感染了三年后就在艺术中发起，然后成功抑制了至少四年的HIV复制。我们将比较完整的全长临时基因组的数量，作为对总潜在依据者的量度，在治疗后两年和四年，以及它如何随时间变化。鉴于许多这些综合病毒可能保持潜在，我们将使用病毒出生测定法测量完整的病毒储存库与复制能力的病毒的数量进行比较。我们将使用深层测序方法来定义从急性感染到治疗倡议的不断发展的病毒群。我们建议，感染三年内的遗传进化足以使我们能够随着时间的流逝而绘制对潜在病毒储藏的相对贡献 建立水库的时间。最后，我们将研究急性感染的免疫激活以及治疗期间如何影响储层的病毒组成。这项研究将估计非洲妇女中潜在水库的建立，规模和稳定性的时机。通过进入急性感染监测的一群年轻女性以及最多五年的艺术，我们可以独特地进行这项研究。将潜在的储层观测扩展到较不发达国家的国家，与发达国家相比，宿主因素，亚型和性别可能有所不同，这将为任何潜在的治疗干预措施提供更广泛的方法的发展。