Cellular factors in gammaretrovirus replication

γ逆转录病毒复制中的细胞因素

• 批准号: 7191483
• 负责人: John A T Young
• 金额: $ 46.74万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191483
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Biological; Cell Communication; Cells; Disease; Endogenous Retroviruses; Enzymes; Family suidae; Future; Gammaretrovirus; Gene Expression; Genome; Goals; HIV-1; Human; Individual; Infection; Inorganic Sulfates; International; Interphase Cell; Learning; Life Cycle Stages; Malignant Neoplasms; Medical; Murine leukemia virus; Mutagenesis; Numbers; Phosphoadenosine Phosphosulfate; Proteins; Reaction; Research; Research Personnel; Retroviridae; Reverse Transcription; Risk; Role playing therapy; Small Interfering RNA; Somatic Cell; Spumavirus; Subfamily lentivirinae; Sus scrofa; Taxonomy; Thinking; Tropism; Unspecified or Sulfate Ion Sulfates; Viral; Virus; Virus Assembly; Virus Diseases; Virus Integration; Virus Replication; Xenograft procedure; Zinc Fingers; base; cell type; insight; novel; pathogen; programs; receptor binding; sulfation; transmission process

DESCRIPTION (provided by applicant): Retroviruses are important viral pathogens of animals and humans, causing a variety of different diseases including cancer and AIDS. Most of these viruses including the gammaretrovirus, murine leukemia virus (MLV), can efficiently infect dividing, but not non-dividing, cell types. By contrast other retroviruses, such as the lentivirus HIV-1, can efficiently infect both dividing and non-dividing cells. We hypothesize that virus- specific interactions with intracellular host cell factors are responsible, at least in part, for this difference in target cell tropism between these retroviruses. To examine this hypothesis we are identifying and characterizing cellular factors which regulate infection by MLV, but not by HIV-1. By performing somatic cell- based mutagenesis studies, as well as the first comprehensive genome-wide siRNA screen of its type, we have made the remarkable observation that there are several hundred novel intracellular factors required for infection by MLV, but not by HIV-1. These findings demonstrate that retroviruses interact with many more cellular factors than was thought previously. The factors involved include ZASC1, a protein containing multiple zinc finger regions, as well as PAPSS1 and PAPSS2, two biosynthetic enzymes that synthesize 3' phosphoadenosine 5' phosphosulfate (PAPS), the high energy sulfate donor used in all sulfation reactions in the cell. The goals of the studies in this proposal include examining the mechanisms of action of ZASC1, and the PAPSS enzymes during MLV infection. We will also determine the steps during MLV replication that are regulated by each of the other cellular factors identified and establish whether these factors also regulate infection by other gammaretroviruses including the pig endogenous retroviruses (PERVs). This research will contribute substantially to our understanding of the roles played by cellular factors during retrovirus replication and should give new insights into why gammaretrovirus infection is restricted only to dividing cell types. Moreover, because of the risk of PERV transmission to humans, during pig to human xenotransplantations, these studies are of immediate medical relevance since they could suggest novel antiviral approaches aimed at disrupting critical gammaretrovirus-host cell factor interactions.

描述（由申请人提供）：逆转录病毒是动物和人类的重要病毒病原体，引起各种不同的疾病，包括癌症和艾滋病。这些病毒中的大多数包括伽马房病毒，鼠白血病病毒（MLV），可以有效地感染细胞类型，但不能有效地感染分裂的细胞类型。相比之下，其他逆转录病毒（例如慢病毒HIV-1）可以有效地感染分裂和非分散细胞。我们假设病毒与细胞内宿主细胞因子的特定相互作用至少部分是因为这些逆转录病毒之间的靶细胞朝向主义差异。为了审查这一假设，我们正在识别和表征细胞因素，这些细胞因子调节MLV的感染，但不能通过HIV-1进行感染。通过进行基于体细胞的诱变研究，以及其类型的首次全面基因组siRNA筛选，我们已经表达了一个显着的观察，即MLV感染了几百个新型细胞内因子，但不是HIV-1。这些发现表明，逆转录病毒与以前想象的更多的细胞因子相互作用。所涉及的因素包括ZASC1，一种含有多个锌指的蛋白质，以及PAPSS1和PAPSS2，两种生物合成酶合成3'磷酸腺苷5'磷酸硫酸盐（PAPS），这是所有硫酸盐供体在细胞中使用的高能量硫酸盐供体。该提案中研究的目标包括检查ZASC1的作用机理，以及MLV感染期间的PAPSS酶。我们还将确定MLV复制过程中由确定的每个其他细胞因子调节的步骤，并确定这些因素是否还调节了其他伽马房病毒感染，包括猪内源性逆转录病毒（PERV）。这项研究将有助于我们对逆转录病毒复制过程中细胞因子扮演的作用的理解，并应提供新的见解，说明为什么伽马环病毒感染仅限于分裂细胞类型。此外，由于猪到人异种移植期间，这些研究具有直接的医学相关性，因为它们可以提出旨在破坏关键的抗病毒方法的新型抗病毒方法，旨在破坏关键的γ-甲状腺病毒 - 宿主 - 宿主 - 宿主 - 宿主相互作用。