MOLECULAR-BASIS OF ORGAN-SPECIFIC SELECTION OF VIRAL VARIANTS DURING CHRONIC INFECTION
MOLECULAR-BASIS OF ORGAN-SPECIFIC SELECTION OF VIRAL VARIANTS DURING CHRONIC INFECTION
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DOI：
10.1128/jvi.65.8.4242-4247.1991
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发表时间：
1991-08-01
影响因子：
5.4
通讯作者：
STRAUSS, JH
中科院分区：
文献类型：
--
作者：
AHMED, R;HAHN, CS;STRAUSS, JH
出生时感染淋巴细胞性脉络膜脑膜炎病毒阿姆斯特朗株的携带者小鼠的中枢神经系统（CNS）和淋巴组织中存在不同表型的病毒变体。 CNS 分离株与亲代病毒相似，会引起成年小鼠的急性感染，而淋巴分离株则会引起与抑制 T 细胞反应相关的慢性感染。 在这项研究中，我们为这种器官特异性选择提供了分子基础，并鉴定了病毒糖蛋白中与组织特异性选择以及变体的持久性和免疫抑制表型相关的单个氨基酸变化。 在绝大多数（47个中的43个）淋巴分离株中观察到病毒糖蛋白260位上的苯丙氨酸（F）到亮氨酸（L）的变化，并且在持续感染小鼠的脾脏中选择了该残基上带有L的变体。 与此形成鲜明对比的是，在同一携带小鼠的 CNS 中，具有亲本序列（残基 260 处的 F）的分离株占主导地位（59 个分离株中的 48 个）。 对几个独立来源（来自不同小鼠）的脾分离株的主要结构基因的完整核苷酸序列分析表明，这些变体与亲本病毒的同一性> 99.8%。 事实上，这些脾分离株中唯一常见的变化是糖蛋白 260 残基处的 F --> L 突变。 这些结果表明，RNA病毒在其自然宿主的慢性感染过程中可以表现出最小的遗传漂变，然而单个或几个突变可以导致与亲本病毒明显不同的变体的器官特异性选择。
Viral variants of different phenotypes are present in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates are similar to the parental virus and cause acute infections in adult mice, whereas the lymphoid isolates cause chronic infections associated with suppressed T-cell responses. In this study, we provide a molecular basis for this organ-specific selection and identify a single amino acid change in the viral glycoprotein that correlates with the tissue specific selection and the persistent and immunosuppressive phenotype of the variants. This phenylalanine (F)-to-leucine (L) change at position 260 of the viral glycoprotein was seen in the vast majority (43 of 47) of the lymphoid isolates, and variants with L at this residue were selected in spleens of persistently infected mice. In striking contrast, isolates with the parental sequence (F at residue 260) predominated (48 of 59 isolates) in the CNS of the same carrier mice. Complete nucleotide sequence analysis of the major structural genes of several independently derived (from different mice) spleen isolates showed that these variants were > 99.8% identical to the parental virus. In fact, the only common change among these spleen isolates was the F --> L mutation at residue 260 of the glycoprotein. These results show that an RNA virus can exhibit minimal genetic drift during chronic infection in its natural host, and yet a single or few mutations can result in the organ-specific selection of variants that are markedly different from the parental virus.