Cellular factors in gammaretrovirus replication

γ逆转录病毒复制中的细胞因素

• 批准号: 7334737
• 负责人: John A T Young
• 金额: $ 43.61万
• 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/7334737
• 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

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.

逆转录病毒是动物和人类的重要病毒病原体，导致多种不同的疾病 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），可以有效地感染划分，但不是非分裂的细胞类型。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裂细胞。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造成这种差异的原因 这些逆转录病毒之间的靶细胞向量。为了审查这一假设，我们正在确定和 表征细胞因子调节MLV的感染，但不是HIV-1。通过进行体细胞 - 我们 已经显着观察到，需要数百个新型细胞内因子 MLV感染，但不是HIV-1。这些发现表明逆转录病毒与更多相互作用 细胞因素比以前想象的。涉及的因素包括ZASC1，一种含有蛋白质的蛋白 多个锌指的区域以及PAPSS1和PAPSS2，两种合成3'的生物合成酶 磷酸腺苷5'磷硫酸盐（PAP），用于所有硫酸盐供体用于所有硫酸盐反应中的高能量供体 细胞。该提案中研究的目标包括检查ZASC1的作用机理， 和MLV感染期间的PAPS酶。我们还将确定MLV复制过程中的步骤 由确定的每个其他细胞因素调节，并确定这些因素是否也调节 其他伽马房病毒感染，包括猪内源性逆转录病毒（PERV）。这项研究会 为我们对逆转录病毒过程中细胞因子扮演的角色的理解做出了重大贡献 复制，应该给出新的见解，说明为什么伽马房病毒感染仅限于分裂细胞 类型。此外，由于在猪到人类期间有perv向人类传播的风险 异种移植，这些研究具有直接的医学相关性，因为它们可以提出新颖 旨在破坏关键伽马甲病毒宿主宿主因子相互作用的抗病毒方法。