Molecular structures and replication fitness of HIV-1 intersubtype recombinants

HIV-1亚型间重组体的分子结构和复制适应性

• 批准号: 7555431
• 负责人: Po San Mario Chin
• 金额: $ 16.41万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555431
• 关键词: AIDS/HIV problem; Affect; Antiviral Therapy; Biological; Biological Assay; Boxing; Cell Culture System; Cell Culture Techniques; Chin; Data; Development; Dimerization; Elements; Evolution; Gagging; Generations; Genetic Recombination; Genomics; Goals; Growth; HIV; HIV vaccine; Human; Indium; Infection; Intervention; Knowledge; Laboratories; Location; Minor; Molecular; Molecular Cloning; Molecular Structure; Mutation; Patients; Pattern; Peptide Signal Sequences; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Population; Public Health; RNA; RNA Viruses; Recombinants; Relapse; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Structure; System; Time; Vaccines; Variant; Vertebral column; Viral; Viral Genome; Virus; Work; World Health Organization; base; fitness; innovation; novel strategies; novel vaccines; pandemic disease; pressure; prevent; programs; smoking cessation; transmission process

DESCRIPTION (provided by applicant): The main hindrance to develop antiviral therapies and effective vaccines for HIV/AIDS is the high variability of the virus. Recombination is a major mechanism that is responsible for this rapid diversification of HIV-1 population. My current research focuses on the mechanisms and restrictions in HIV-1 intersubtype recombination. We have shown that the dimerization initiation signal (DIS) sequence is a major determinant of intersubtype recombination and that the DIS has an important function in maintaining dimeric RNA structure important for recombination. To further understand the role of recombination in HIV-1 evolution, we investigate how recombination contributes to the generation of recombinants with altered replication fitness. Our long-term goal is to elucidate the elements in the viral genome that affect replication fitness of a HIV-1 recombinant. These viral elements represent new potential targets for blocking or enhancing recombination that can affect the continuous replication of HIV-1 in the host. The objectives of this application are to reveal 1) the proportion of recombinants generated in cell culture and patients that are viable, 2) the ratios at which these recombinants will have better, equal and worse replication fitness compared to wildtype and 3) the elements in viral genome that determine replication fitness. The central hypothesis is that newly generated HIV-1 intersubtype recombinants have an array of replication fitness and there is a finite window for HIV-1 replication fitness allowing the recombinants to continue to replicate in the host. This hypothesis is based on the observations that CRF02_AG has a higher replication fitness than the parental subtypes A and G HIV-1 and that our preliminary data demonstrated recombination between subtypes B and C HIV-1 can generate recombinant with altered replication fitness. The rationale of the proposed research is that characterizing the replication fitness of HIV-1 intersubtype recombinants will allow us to further understand the molecular mechanisms for generating new HIV-1 recombinant strains with biological advantages. The Specific Aims are to i) determine the replication fitness of cell culture-derived HIV-1 intersubtype recombinants, ii) identify the location of crossover junctions of patient-derived HIV-1 intersubtype recombinants, and iii) characterize the replication fitness of patient-derived HIV-1 intersubtype recombinants. The proposed research is relevant to public health because the identified viral elements that determine replication fitness may represent new targets for developing strategies to prevent the continuous replication of HIV-1 in the human hosts.

描述（由申请人提供）：开发针对艾滋病毒/艾滋病的抗病毒疗法和有效疫苗的主要障碍是病毒的高度变异性。重组是导致HIV-1群体快速多样化的主要机制。我目前的研究重点是HIV-1亚型间重组的机制和限制。我们已经证明，二聚化起始信号（DIS）序列是亚型间重组的主要决定因素，并且DIS在维持重组所需的二聚体RNA结构方面具有重要功能。为了进一步了解重组在HIV-1进化中的作用，我们研究了重组如何导致复制适应性改变的重组体的产生。我们的长期目标是阐明病毒基因组中影响HIV-1重组病毒复制适应性的元素。这些病毒元件代表了阻断或增强重组的新潜在靶标，这些重组可以影响HIV-1在宿主体内的持续复制。本应用程序的目的是揭示1)在细胞培养和患者中产生的可存活的重组体的比例，2)与野生型相比，这些重组体具有更好，相同和更差的复制适应性的比例，以及3)病毒基因组中决定复制适应性的元素。核心假设是新产生的HIV-1亚型间重组具有一系列复制适应度，并且HIV-1复制适应度有一个有限的窗口，允许重组在宿主中继续复制。这一假设是基于观察到CRF02_AG比亲本亚型a和G HIV-1具有更高的复制适应度，并且我们的初步数据表明，B和C亚型HIV-1之间的重组可以产生具有改变复制适应度的重组。本研究的基本原理是，表征HIV-1亚型间重组体的复制适应性将使我们进一步了解产生具有生物学优势的新HIV-1重组株的分子机制。具体目的是：1)确定细胞培养源性HIV-1亚型间重组的复制适应性，2)确定患者源性HIV-1亚型间重组交叉连接的位置，以及3)表征患者源性HIV-1亚型间重组的复制适应性。拟议的研究与公共卫生相关，因为确定的决定复制适应性的病毒元件可能代表开发策略以防止HIV-1在人类宿主中持续复制的新目标。