Differences in the susceptibility of herpes simplex virus types 1 and 2 to modified heparin compounds suggest serotype differences in viral entry
Differences in the susceptibility of herpes simplex virus types 1 and 2 to modified heparin compounds suggest serotype differences in viral entry
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DOI：
10.1128/jvi.70.6.3461-3469.1996
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发表时间：
1996-06-01
影响因子：
5.4
通讯作者：
Shulman, N
中科院分区：
文献类型：
--
作者：
Herold, BC;Gerber, SI;Shulman, N
尽管硫酸乙酰肝素 (HS) 是 1 型单纯疱疹病毒 (HSV-1) 和 HSV-2 与细胞表面结合的初始受体，但这两种血清型在流行病学、细胞向性和体外竞争病毒受体的能力方面有所不同。这些观察结果不一定矛盾，如果这两种血清型识别 HS 的不同结构特征，则可以解释这些观察结果。为了比较 HS 对 HSV-1 和 HSV-2 结合和感染重要的具体特征，我们利用肝素和细胞表面 HS 之间的结构相似性，并比较化学修饰的肝素化合物抑制噬菌斑形成的能力，我们发现肝素对两种血清型的抗病毒活性独立于抗凝血活性，此外，多糖的特定带负电荷区域，包括 N 硫酸化和羧基，是相互作用的关键结构特征由于N脱硫或羧基还原消除了肝素的抗病毒活性，HSV-1和HSV-2都与细胞表面发生了变化，相反，6-O硫酸化和2-,3-O硫酸化是HSV-1感染的重要决定因素，O-脱硫肝素对HSV-1感染几乎没有或没有抑制作用，但抑制HSV-2感染。使用一系列型间重组突变病毒，我们发现对 O-脱硫肝素的敏感性可通过 HSV-2 的糖蛋白 C (gC-2) 基因转移至 HSV-1，这支持了 HSV-1 和 HSV-2 的包膜糖蛋白与肝素的不同结构特征以不同亲和力相互作用的观点。为了确定修饰的肝素化合物是否通过与细胞表面 HS 竞争病毒附着来抑制斑块形成，还进行了结合研究。然而，在 4°C 的初始附着期间，几种化合物抑制了 HSV-1 与细胞的结合；当细胞和接种物温度转移至 37°C 时，这种抑制作用被逆转。这种对修饰肝素化合物的温度依赖性差异反应主要在病毒体包膜中存在 HSV-1 糖蛋白 C (gC-1) 时明显。删除 gC-1 的 HSV-1 和 HSV-2 的温度依赖性差异最小。这些结果表明 HSV-1 和 HSV-2 与细胞表面 HS 相互作用的差异可能会影响细胞向性。
Although heparan sulfate (HS) serves as an initial receptor for the binding of both herpes simplex virus type 1 (HSV-1) and HSV-2 to cell surfaces, the two serotypes differ in epidemiology, cell tropism, and ability to compete for viral receptors in vitro, These observations are not necessarily contradictory and can be explained if the two serotypes recognize different structural features of HS. To compare the specific features of HS important for the binding and infection of HSV-1 and HSV-2, we took advantage of structural similarities between heparin and cell surface HS and compared the abilities of chemically modified heparin compounds to inhibit plaque formation, We found that the antiviral activity of heparin for both serotypes was independent of anticoagulant activity, Moreover, specific negatively charged regions of the polysaccharide, including N sulfations and the carboxyl groups, are key structural features for interactions of both HSV-1 and HSV-2 with cell surfaces since N desulfation or carboxyl reduction abolished heparin's antiviral activity, In contrast, 6-O sulfations and 2-,3-O sulfations are important determinants primarily for HSV-1 infection, The O-desulfated heparins had little or no inhibitory effect on HSV-1 infection but inhibited HSV-2 infection, Using a series of intertypic recombinant mutant viruses, we found that susceptibility to O-desulfated heparins can be transferred to HSV-1 by the gene for glycoprotein C of HSV-2 (gC-2), This supports the notion that the envelope glycoproteins of HSV-1 and HSV-2 interact with different affinities for different structural features of heparin, To determine if the modified heparin compounds inhibited plaque formation by competing with cell surface HS for viral attachment, binding studies were also performed, As anticipated, most compounds inhibited binding and plaque formation in parallel, However, several compounds inhibited the binding of HSV-1 to cells during the initial attachment period at 4 degrees C; this inhibitory effect was reversed when the cells and inoculum were shifted to 37 degrees C, This temperature-dependent differential response to modified heparin compounds was evident primarily when glycoprotein C of HSV-1 (gC-1) was present in the virion envelope, Minimal temperature-dependent differences were seen for HSV-1 with gC-1 deleted and for HSV-2. These results suggest differences in the interactions of HSV-1 and HSV-2 with cell surface HS that may influence cell tropism.