Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIVSF162P3 maps to envelope gp120
Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIVSF162P3 maps to envelope gp120
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DOI：
10.1128/jvi.77.2.989-998.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Cheng-Mayer, C
中科院分区：
文献类型：
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作者：
Hsu, M;Harouse, JM;Cheng-Mayer, C
通过体内的快速连续转移，嵌合的嗜CCR 5的猿猴/人免疫缺陷病毒SHIVSF 162从非致病性的并且在阴道粘膜中传播性差的病毒进化为仍然保持CCR 5使用但现在是致病性的并且有效地建立阴道内感染的变体。为了确定是否包膜糖蛋白gp 120是负责增加的致病性和传播的变体SHIVSF 162 P3，我们克隆和测序的优势包膜基因（编码P3 gp 120），并在体外的功能。还构建了表达致病性变体的P3 gp 120的嵌合SHIVSF 162病毒，命名为SHIVSF 162 PC，并评估其体内致病性和粘膜传播性。我们发现，与野生型SHIVSF 162 gp 120相比，P3 gp 120赋予体外中和抗性并增加病毒的进入效率，但其融合诱导能力受到损害。在体内，SHIVSF 162 PC感染两个和两个三只恒河猴的静脉注射和阴道内途径，分别。然而，尽管在一些感染动物中，峰值病毒血症达到每毫升血浆10（6）至10（7）个RNA拷贝，并且与肠道相关CD 4（+）淋巴细胞的耗竭相关，但没有动物保持预测疾病进展的病毒设定点。总之，本研究的数据表明，病毒致病性包膜糖蛋白的进入效率和细胞病变特性之间缺乏相关性。此外，尽管env gp 120含有SHIVSF 162 P3的增强的粘膜传递性的决定因素，但其增加的毒力的决定因素可能需要env gp 41中的额外序列改变和/或映射到其他病毒基因。
Through rapid serial transfer in vivo, the chimeric CCR5-tropic simian/human immunodeficiency virus SHIVSF162 evolved from a virus that is nonpathogenic and poorly transmissible across the vaginal mucosa to a variant that still maintains CCR5 usage but which is now pathogenic and establishes intravaginal infection efficiently. To determine whether envelope glycoprotein gp120 is responsible for increased pathogenesis and transmissibility of the variant SHIVSF162P3, we cloned and sequenced the dominant envelope gene (encoding P3 gp120) and characterized its functions in vitro. Chimeric SHIVSF162 virus expressing P3 gp120 of the pathogenic variant, designated SHIVSF162PC, was also constructed and assessed for its pathogenicity and mucosal transmissibility in vivo. We found that, compared to wild-type SHIVSF162 gp120, P3 gp120 conferred in vitro neutralization resistance and increased entry efficiency of the virus but was compromised in its fusion-inducing capacity. In vivo, SHIVSF162PC infected two of two and two of three rhesus macaques by the intravenous and intravaginal routes, respectively. Nevertheless, although peak viremia reached 10(6) to 10(7) RNA copies per ml of plasma in some infected animals and was associated with depletion of gut-associated CD4(+) lymphocytes, none of the animals maintained a viral set point that would be predictive of progression to disease. Together, the data from this study suggest a lack of correlation between entry efficiency and cytopathic properties of envelope glycoproteins with viral pathogenicity. Furthermore, whereas env gp120 contains the determinant for enhanced mucosal transmissibility of SHIVSF162P3, the determinant(s) of its increased virulence may require additional sequence changes in env gp41 and/or maps to other viral genes.