Ongoing replication may occur on HAART

HAART 上可能会发生持续复制

• 批准号: 8012525
• 负责人: Una T O'Doherty
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012525
• 关键词: Address; Antigen Presentation; Antiviral Therapy; Applications Grants; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Cycle; Cells; Clinical; DNA; Data; Dendritic Cells; Evolution; Figs - dietary; Gastrointestinal tract structure; Goals; HIV; HIV Infections; Half-Life; Highly Active Antiretroviral Therapy; Human immunodeficiency virus test; In Vitro; Individual; Infection; Institution; Life; Maintenance; Measures; Memory; Methods; Monitor; Mononuclear; Pathogenesis; Patients; Proliferating; Relative (related person); Residual state; Resistance; Rest; Site; Sorting - Cell Movement; T-Cell Activation; T-Lymphocyte Subsets; Testing; Time; Viral; Viral Load result; Viral Proteins; improved; in vivo; killings; lymph nodes; public health relevance; research study; theories; viral DNA

DESCRIPTION (provided by applicant): HIV-infected individuals accumulate a reservoir of treatment-resistant, latently infected resting CD4+ T cells, even when therapy is started shortly after exposure. It remains unclear how treatment resistant HIV viral reservoirs are maintained. One theory is that latently infected cells are established early in infection and that these cells persist in the presence of HAART. A second theory is that a very low level of HIV replication is required for viral persistence. The goal of this application is to determine if ongoing replication can be demonstrated to occur in the presence of HAART. If this can be demonstrated to occur then it should be considered as a potential mechanism for reservoir maintenance. Distinguishing between these theories is important because it will drive what approaches we should take if HIV infection is to be eradicated from infected patients. However, regardless of the mechanism(s) of reservoir maintenance or the approaches to eradication of HIV, assays that detect ongoing HIV replication would be useful for monitoring therapy. In an effort to assess if ongoing replication occurs in patients on HAART, we propose to monitor total and integrated HIV DNA over time after initiating HAART. The idea behind the proposal is that in the absence of ongoing replication total DNA should eventually equal integrated HIV DNA. We will measure total and integrated HIV DNA in mononuclear cells in both blood and the GI tract and test if an excess correlates with independent measures of ongoing replication (Aim1A). In addition, we will measure these intermediates within subsets of these cells (Aim1B). Finally, we will take a complementary approach to determine if ongoing replication occurs by testing for viral spread to short lived cells (Aim1C). We expect our experiments will provide information on whether ongoing replication occurs in HIV infected individuals on HAART and potentially new information on HIV pathogenesis. PUBLIC HEALTH RELEVANCE: It is unclear why HIV is treatable, but not curable. It appears that there is a treatment resistant reservoir, but how this reservoir is maintained in the presence of HAART is unclear. In this grant proposal, we try to address this question by determining if HIV replication is completely stopped with antiviral therapy. We propose experiments that attempt to answer this question by measuring viral DNA intermediates over time on antiviral therapy.

描述（由申请人提供）：感染HIV的个体即使在暴露后不久就开始治疗，也会积累耐药的，潜在感染的静息CD4+ T细胞的水库。目前尚不清楚如何维持耐药的HIV病毒储存剂。一种理论是，潜在感染的细胞在感染的早期建立，并且这些细胞在HAART存在下持续存在。第二个理论是，病毒持久性需要非常低的HIV复制。该应用的目的是确定是否可以在HAART存在下证明正在进行的复制。如果可以证明这种情况发生，则应将其视为储层维持的潜在机制。区分这些理论很重要，因为如果要从感染患者中消除HIV感染，我们将采取什么方法。但是，无论储层维持的机制或消除HIV的方法如何，检测正在进行的HIV复制的测定方法将有助于监测治疗。为了评估HAART患者是否发生了持续的复制，我们建议在启动HAART后随着时间的推移监测总和HIV DNA。该提案背后的想法是，在没有持续的复制的情况下，总DNA最终应等于综合的HIV DNA。我们将测量血液和胃肠道单核细胞中的总HIV DNA，并测试过量与持续复制的独立测量（AIM1A）是否相关（AIM1A）。此外，我们将在这些细胞的子集中测量这些中间体（AIM1B）。最后，我们将采用一种补充方法来确定是否通过测试病毒扩散到短活细胞（AIM1C）来进行持续的复制。我们预计我们的实验将提供有关在HAART上感染了HIV感染的个体以及有关HIV发病机理的新信息的信息。 公共卫生相关性：目前尚不清楚为什么艾滋病毒是可以治疗的，但不能治愈。看来有一个耐药的储层，但是在Haart存在下如何保持该储层尚不清楚。在这项赠款建议中，我们试图通过确定抗病毒疗法是否完全停止艾滋病毒复制来解决这个问题。我们提出的实验试图通过在抗病毒疗法上测量病毒DNA中间体来回答这个问题。