3-羟基邻苯二甲酰基β-乳球蛋白。IV. 生殖器疱疹病毒感染小鼠模型中的抗病毒活性

3-Hydroxyphthaloyl beta-lactoglobulin. IV Antiviral activity in the mouse model of genital herpesvirus infection.

作者信息

Kokuba H, Aurelian L, Neurath A R

机构信息

Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

出版信息

Antivir Chem Chemother. 1998 Jul;9(4):353-7.

PMID:9875414

Abstract

The spread of sexually transmitted infections caused by herpes simplex virus type 2 (HSV-2) has continued unabated despite educational efforts generated in response to the human immunodeficiency virus (HIV) epidemic. Given the absence of effective vaccines, this indicates the need to develop prophylactic measures such as topical antiviral agents. Chemical modification of bovine beta-lactoglobulin (beta-LG), the major protein of whey, by hydroxyphthalic anhydride (3HP) led to the generation of a potent HIV-1 inhibitor designated 3HP-beta-LG. This agent was shown to also have antiviral activity against HSV-2 and HSV-1 in vitro. Recent studies indicate that 3HP-beta-LG binds to HSV-1 virions, which, at least in part, involves the viral glycoprotein gE. Here we show that 3HP-beta-LG inhibits HSV-2 infection in the mouse model of genital HSV-2 infection. Simultaneous exposure to HSV-2 and 3HP-beta-LG caused a significant decrease in the proportion of infected animals (27% virus shedding, 5% lesion development and 0% fatality for 3HP-beta-LG as compared to 80% shedding, 60% lesion development and 53% fatality in mice treated with PBS). The proportion of animals with HSV-2 infection after treatment with beta-LG was similar to that in the PBS-treated group. Pretreatment with 3HP-beta-LG formulated in a gel, which prolongs the presence of the agent in the vagina, also significantly reduced the proportion of HSV-2-infected mice (5% virus shedding, 5% lesion development and 0% fatality for 3HP-beta-LG as compared to 70% shedding, 60% lesion development and 40% fatality in vehicle-treated mice). These differences were significant (P < or = 0.0005, 0.002 and 0.008 for shedding, lesion development and fatality, respectively). Virus titres in the minority of mice that developed infection were similar to those in untreated mice. HSV-2 infection was not inhibited by treatment of an ongoing infection, indicating that 3HP-beta-LG interferes with the initial infection. These data suggest that 3HP-beta-LG may be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections.

摘要

尽管针对人类免疫缺陷病毒（HIV）流行开展了教育工作，但由2型单纯疱疹病毒（HSV - 2）引起的性传播感染仍在持续蔓延。鉴于缺乏有效的疫苗，这表明需要开发诸如局部抗病毒药物等预防措施。用羟基邻苯二甲酸酐（3HP）对乳清中的主要蛋白质牛β - 乳球蛋白（β - LG）进行化学修饰，产生了一种名为3HP - β - LG的强效HIV - 1抑制剂。该药物在体外也显示出对HSV - 2和HSV - 1的抗病毒活性。最近的研究表明，3HP - β - LG与HSV - 1病毒粒子结合，这至少部分涉及病毒糖蛋白gE。在此我们表明，3HP - β - LG在生殖器HSV - 2感染的小鼠模型中抑制HSV - 2感染。同时暴露于HSV - 2和3HP - β - LG导致感染动物的比例显著降低（3HP - β - LG组病毒脱落率为27%，损伤发生率为5%，死亡率为0%；相比之下，用磷酸盐缓冲液（PBS）处理的小鼠病毒脱落率为80%，损伤发生率为60%，死亡率为53%）。用β - LG处理后感染HSV - 2的动物比例与PBS处理组相似。用凝胶制剂的3HP - β - LG进行预处理可延长药物在阴道中的存在时间，这也显著降低了HSV - 2感染小鼠的比例（3HP - β - LG组病毒脱落率为5%，损伤发生率为5%，死亡率为0%；相比之下，用赋形剂处理的小鼠病毒脱落率为70%，损伤发生率为60%，死亡率为40%）。这些差异具有统计学意义（病毒脱落、损伤发生和死亡的P值分别≤0.0005、0.002和0.008）。少数发生感染的小鼠中的病毒滴度与未处理小鼠相似。3HP - β - LG对正在进行的感染没有抑制作用，这表明3HP - β - LG干扰初始感染。这些数据表明，3HP - β - LG可能是预防生殖器疱疹病毒感染阴道传播的有效药物。