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（由申请人提供）：需要终生治疗来维持对 HIV 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 数百万人需要治疗是一个主要问题，唯一的替代方案是制定一种可以从体内根除艾滋病毒的策略，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。这些发现凸显了实现艾滋病毒持久治愈的潜力，并引起了该领域的极大兴趣。仍然需要确定影响其大小和稳定性的因素，特别是在疾病负担最严重的撒哈拉以南非洲人群中，我们建议分析潜伏病毒库的成分随时间的变化，这将告诉我们病毒何时沉积在病毒库中，以及可能的情况。该项目将调查 20 名 C 亚型感染的南非妇女，她们在感染三年后开始接受 ART，并在此后成功抑制 HIV 复制至少四年。完好无损的数量治疗开始后两年和四年的全长原病毒基因组，作为总潜在病毒库的衡量标准，以及它如何随时间变化。鉴于许多整合病毒可能仍然存在，我们将比较完整的晚期原病毒库。通过使用病毒生长来测量具有复制能力的病毒的数量，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病毒群的进化。足够的t允许我们绘制了随着时间的推移对潜在原病毒库的相对贡献以及 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潜伏病毒库的病毒组成。我们处于独特的地位，通过对一组接受急性感染监测的年轻女性进行这项研究，并将潜伏病毒库观察扩展到宿主因素、亚型的欠发达国家群体。与发达国家相比，性别可能有所不同各国将为任何潜在的治疗干预措施制定更通用的方法提供信息。