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; 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）：开发抗病毒疗法和艾滋病毒/艾滋病有效疫苗的主要障碍是病毒的高度差异。重组是造成HIV-1人群快速多样化的主要机制。我目前的研究重点是HIV-1 Intersubtype重组的机制和限制。我们已经表明，二聚启动信号（DIS）序列是subtype重组的主要决定因素，并且DIS在维持对重组重要的二聚体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有助于复制适应性改变的重组者的产生。我们的长期目标是阐明影响HIV-1重组的复制适应性的病毒基因组中的元素。这些病毒元素代表了阻断或增强重组的新潜在靶标，这些靶标可能会影响宿主中HIV-1的连续复制。本应用的目的是揭示1）在细胞培养物和可行的患者中产生的重组的比例，2）与野生型相比，这些重组者具有更好，相等和更差的复制适应性的比率，以及与野生型相比，3）病毒基因组中确定复制适应性的元素。中心假设是新生成的HIV-1 Intersubtype重组具有一系列复制适应性，并且有一个有限的HIV-1复制适应性窗口，使重组者可以继续在主机中复制。该假设是基于观察结果，即CRF02_AG的复制适应性比父母亚型A和G HIV-1更高，并且我们的初步数据表明亚型B和C HIV-1之间的重组可以使重组与复制适应性改变。拟议研究的理由是，表征HIV-1 Intersubtype重组剂的复制适应性将使我们能够进一步了解具有生物学优势的新型HIV-1重组菌株的分子机制。具体目的是i）确定细胞培养的HIV-1 IntersubType重组的复制适应性，II）确定患者衍生的HIV-1 Intersubtype重新组合剂的交叉连接的位置，以及III）表征患者衍生的HIV HIV-1跨性别重组的复制适应性。拟议的研究与公共卫生有关，因为确定复制适应性的已确定的病毒元素可能代表了制定策略以防止人类宿主中HIV-1持续复制的新目标。