Quasispecies Evolution During Lentivirus Persistence

慢病毒持续存在期间的准种进化

• 批准号: 6604159
• 负责人: Susan L Carpenter
• 金额: $ 14.6万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604159
• 关键词: Lentivirus; Retroviridae disease; equine infectious anemia virus; evolution; gene environment interaction; gene expression; gene mutation; genotype; horses; host organism interaction; immunity; longitudinal animal study; mathematical model; pathologic process; phenotype; provirus; statistics /biometry; virus genetics; virus protein; virus replication

DESCRIPTION (provided by applicant): The long range goal of these studies is to delineate viral determinants of lentivirus disease and persistence. Genetic diversity is a hallmark of lentivirus infections. In vivo populations of virus are comprised of a heterogeneous mix of related genotypic and phenotypic variants, each with the potential to become dominant in the face of environmental change. The goal of this study is to determine if virus variants with altered replication fitness are preferentially selected during periods of immune maturation and clinical latency. As lentiviruses are already known to vary in env with disease progression, this study may provide the first definitive evidence that other genes are selected in association with changes in the host immune environment. This pilot study will utilize the well-characterized equine infectious anemia virus (EIAV) model to test the hypothesis that immune maturation and the onset of clinical quiescence are associated with selection of viral variants with decreased Rev activity. In the first specific aim, retrospective samples from EIAV-infected horses will be used in longitudinal and cross-sectional analyses of Rev quasispecies during clinical disease. Genetic and computational tools will establish the general patterns of quasispecies evolution at different stages of clinical disease and immune maturation. In the second specific aim, Rev genotypes identified in Specific Aim 1 will be functionally characterized in transient expression assays. The quasispecies Rev phenotype will be determined using a weighted average of the activity of individual variants, and statistical analyses will determine if changes in quasispecies Rev phenotype correlate with specific stages of clinical disease. Rev chimeric proviruses will be constructed to determine the effect of Rev variation on virus replication. The third specific aim will develop a mathematical model of phenotype variation and immune maturation to explore in silico the hypothesis that less fit variants may be selected in a host with a mature immune response. Completion of these studies will demonstrate the importance of secondary loci in disease progression, reveal the biological relevance and utility of multi-locus modets, and form a basis for more realistic and complex models that include additional virus and host parameters of disease progression.

描述（由申请方提供）：这些研究的长期目标是描述慢病毒疾病和持久性的病毒决定因素。遗传多样性是慢病毒感染的标志。体内病毒群体由相关基因型和表型变体的异质混合物组成，每种变体都有可能在环境变化中占主导地位。本研究的目的是确定在免疫成熟和临床潜伏期期间是否优先选择具有改变的复制适应性的病毒变体。由于慢病毒已经知道随着疾病的进展而改变env，这项研究可能提供第一个明确的证据，表明其他基因的选择与宿主免疫环境的变化有关。本初步研究将利用充分表征的马传染性贫血病毒（EIAV）模型来检验免疫成熟和临床静止期的开始与选择Rev活性降低的病毒变体相关的假设。在第一个特定目标中，将使用来自EIAV感染马的回顾性样本对临床疾病期间的Rev准种进行纵向和横断面分析。遗传和计算工具将建立准种在临床疾病和免疫成熟的不同阶段进化的一般模式。在第二个特定目的中，将在瞬时表达试验中对特定目的1中鉴定的Rev基因型进行功能表征。将使用个体变体活性的加权平均值确定准种Rev表型，统计分析将确定准种Rev表型的变化是否与临床疾病的特定阶段相关。将构建Rev嵌合前病毒以确定Rev变异对病毒复制的影响。第三个具体目标将开发表型变异和免疫成熟的数学模型，以通过计算机模拟探索以下假设：在具有成熟免疫应答的宿主中可以选择不太适合的变体。这些研究的完成将证明次要基因座在疾病进展中的重要性，揭示多基因座模型的生物学相关性和实用性，并为包括疾病进展的其他病毒和宿主参数的更现实和复杂的模型奠定基础。

项目成果

Analysis of the EIAV Rev-responsive element (RRE) reveals a conserved RNA motif required for high affinity Rev binding in both HIV-1 and EIAV.

• DOI: 10.1371/journal.pone.0002272
• 发表时间: 2008-06-04
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lee JH;Culver G;Carpenter S;Dobbs D
• 通讯作者: Dobbs D

Identifying interaction sites in "recalcitrant" proteins: predicted protein and RNA binding sites in rev proteins of HIV-1 and EIAV agree with experimental data.

• DOI: 10.1142/9789812701626_0038
• 发表时间: 2006-01-01
• 期刊: Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
• 作者: Terribilini, Michael;Lee, Jae-Hyung;Dobbs, Drena
• 通讯作者: Dobbs, Drena

Immune selection of equine infectious anemia virus env variants during the long-term inapparent stage of disease.

• DOI: 10.1016/j.virol.2007.01.037
• 发表时间: 2007-06
• 期刊: Virology
• 影响因子: 3.7
• 作者: B. Sponseller;Wendy O. Sparks;Y. Wannemuehler;Yuxing Li;Amanda K. Antons;J. Oaks;S. Carpenter

Structural model of the Rev regulatory protein from equine infectious anemia virus.

• DOI: 10.1371/journal.pone.0004178
• 发表时间: 2009
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Ihm, Yungok;Sparks, Wendy O.;Lee, Jae-Hyung;Cao, Haibo;Carpenter, Susan;Wang, Cai-Zhuang;Ho, Kai-Ming;Dobbs, Drena
• 通讯作者: Dobbs, Drena

Naturally arising point mutations in non-essential domains of equine infectious anemia virus Rev alter Rev-dependent nuclear-export activity.

马传染性贫血病毒Rev非必需结构域中自然产生的点突变改变了Rev依赖性核输出活性。

• DOI: 10.1099/vir.0.83195-0
• 发表时间: 2008
• 期刊: The Journal of general virology
• 作者: Sparks,WendyO;Dorman,KarinS;Liu,Sijun;Carpenter,Susan
• 通讯作者: Carpenter,Susan