Evolution of a simian immunodeficiency virus pathogen
Evolution of a simian immunodeficiency virus pathogen
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DOI：
10.1128/jvi.72.1.405-414.1998
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发表时间：
1998-01-01
影响因子：
5.4
通讯作者：
Mullins, JI
中科院分区：
文献类型：
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作者：
Edmonson, P;MurpheyCorb, M;Mullins, JI
猴免疫缺陷病毒（SIV）在猕猴中的疾病诱导分析最初因缺乏分子定义的致病株而受阻。第一个接种到猕猴体内的分子克隆SIV株，SIVmacBK 28和SIVmacBK 44（以下分别命名为BK 28和BK 44），就是这样的例子，因为它们在任何接种动物中接种后1年内都没有诱发疾病。在这里，我们报告的自然历史的感染与BK 28和BK 44在接种恒河猴和努力增加致病性的BK 28通过遗传操作和体内传代。BK 44感染在4只感染超过7年的动物中没有导致疾病，而BK 28在监测长达7年的动物中不到一半的动物中引起疾病。通过在人类细胞中先前传代而截短的BK 28跨膜蛋白（TM）编码序列的延长略微增加了致病性，四只动物中的两只在感染的第三年死亡，一只在感染的第七年死亡。修改BK 28长末端重复序列，包括四个共识核因子SP 1和两个共识NF-κ B结合位点增强早期病毒复制，而不增加致病性。相反，从第一只死于免疫缺陷疾病的动物体内传代BK 28（感染后1.5年），产生了一致的致病性毒株，50%存活时间约为1.3年，因此对应于迄今为止鉴定的最致病的SIV毒株之一。为了确定致病性是否需要在体内传代过程中进化的不同病毒准种，或者是否已经进化出毒性更强的病毒变体，我们产生了由来自体内传代病毒（H824）的病毒基因组的3'半与BK 28基因组的5'半融合组成的分子克隆。该克隆病毒（BK 28/H824）的疾病诱导动力学与体内传代病毒相似，5只动物中有4只存活不到1.7年。因此，致病性增强的变异株的进化可以解释该SIV株致病性增强的原因。导致这种毒性转化的遗传变化包括最多59个点突变和3个长度变化突变。关键突变可能是多个和分散的，包括TM和Nef编码序列的延长; RNA剪接供体和受体位点、TATA盒位点和Sp1位点的变化; SU V2区的多个变化，包括一个共有中和表位; SU中5个新的N-连接糖基化位点。
Analysis of disease induction by simian immunodeficiency viruses (SIV) in macaques was initially hampered by a lack of molecularly defined pathogenic strains. The first molecularly cloned SIV strains inoculated into macaques, SIVmacBK28 and SIVmacBK44 (hereafter designated BK28 and BK44, respectively), were cases in point, since they failed to induce disease within 1 year postinoculation in any inoculated animal. Here we report the natural history of infection with BK28 and BK44 in inoculated rhesus macaques and efforts to increase the pathogenicity of BK28 through genetic manipulation and in vivo passage. BK44 infection resulted in no disease in four animals infected for more than 7 years, whereas BK28 induced disease in less than half of animals monitored for up to 7 years. Elongation of the BK28 transmembrane protein (TM) coding sequence truncated by prior passage in human cells marginally increased pathogenicity, with two of four animals dying in the third year and one dying in the seventh year of infection. Modification of the BK28 long terminal repeat to include four consensus nuclear factor SP1 and two consensus NF-kappa B binding sites enhanced early virus replication without augmenting pathogenicity. In contrast, in vivo passage of BK28 from the first animal to die from immunodeficiency disease (1.5 years after infection) resulted in a consistently pathogenic strain and a 50% survival time of about 1.3 years, thus corresponding to one of the most pathogenic SIV strains identified to date. To determine whether the diverse viral quasispecies that evolved during in vivo passage was required for pathogenicity or whether a more virulent virus variant had evolved, we generated a molecular clone composed of the 3' half of the viral genome derived from the in vivo-passaged virus (H824) fused with the 5' half of the BK28 genome. Kinetics of disease induction with this cloned virus (BK28/H824) were similar to those with the in vivo-passaged virus, with four of five animals surviving less than 1.7 years. Thus, evolution of variants,vith enhanced pathogenicity can account for the increased pathogenicity of this SIV strain. The genetic changes responsible for this virulent transformation included at most 59 point mutations and 3 length-change mutations. The critical mutations were likely to have been multiple and dispersed, including elongation of the TM and Nef coding sequences; changes in RNA splice donor and acceptor sites, TATA box sites, and Sp1 sites; multiple changes in the V2 region of SU, including a consensus neutralization epitope; and five new N-linked glycosylation sites in SU.