Immunostimulatory CpG treatment for genital HSV-2 infections
Immunostimulatory CpG treatment for genital HSV-2 infections
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DOI：
10.1093/jac/dkg481
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发表时间：
2003-12-01
影响因子：
5.2
通讯作者：
Pyles, RB
中科院分区：
文献类型：
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作者：
Herbst, MM;Pyles, RB
生殖器单纯疱疹病毒2型（HSV-2）感染是最常见的性传播疾病之一，感染了大约20-30%的美国成年人。2尽管通过行为改变和化学干预措施努力降低2型单纯疱疹病毒的传播率，但最近报告的血清患病率增加了30% 3，这表明这种流行病的持续性质和目前治疗方法的不足。原发性HSV-2感染产生囊性溃疡性病变，并在支配感觉神经元中建立终身潜伏感染。由病毒再激活引起的复发性溃疡性病变易受人类免疫缺陷病毒1型（HIV-1）感染和其他病原体定植。5,6病毒再激活也会导致无症状的病毒脱落，这是病毒传播的一个主要因素。大多数hsv -2血清阳性的人没有意识到他们被感染，并且可以在没有临床明显病变的情况下传播病毒，进一步使感染控制复杂化。这种无症状的病毒脱落事件发生频率高达40%的采样日，通过PCR测量。5,7理想情况下，有效的治疗方法不仅要尽量减少原发和复发疾病的严重程度和持续时间，而且要减少病毒从生殖器粘膜的脱落，以降低传播率。诺贝尔奖获得者格特鲁德·埃利恩和她的同事介绍了一种最成功的化学干预方法，该方法基于病毒胸苷激酶（TK）的混杂性及其核苷类似物的磷酸化。被激活的类似物的掺入终止了病毒DNA基因组的合成。埃利恩研究中的先导化合物阿昔洛韦（Aciclovir）被广泛使用；然而，低生物利用度需要高剂量和不方便的给药方案，导致依从性差和治疗失败。阿昔洛韦和其他核苷类似物的衍生物已被确定具有更好的特征，但也需要多种给药方案。最近，慢性抑制药物治疗（如伐昔洛韦，3-5剂量/天终身服用）已被报道可减少隐性病毒脱落和可能的传播。当剂量适当时，目前的干预措施可以适度减少病变持续时间，并且只有慢性抑制治疗才能减少病毒脱落，这表明需要改进或协同干预策略。多种高剂量方案和针对病毒功能（如TK）的特异性靶向可以选择具有适应性突变的后代，从而产生抗病毒抗性。正如预测的那样，HSV-2抗病毒耐药病毒正变得越来越普遍，特别是在免疫功能低下的患者中。10 .人们对评价通过使用局部杀微生物剂来预防2型单纯疱疹病毒和其他生殖器病原体传播的方法的工作越来越感兴趣。这种化合物的作用是阻止病毒附着或阻止病毒进入宿主细胞。11理想的杀微生物剂应该是安全有效、检测不到、价格低廉、对各种病原体有广泛效力的。临床前研究表明，如果在病原体暴露之前或之后立即给予这些化合物是有效的，限制了方便和隐蔽的应用。一些候选杀微生物剂正在临床评估中；然而，目前在动物模型中没有一种显示出对2型单纯疱疹病毒有效的水平。此外，评估中的许多杀菌剂具有避孕作用，因此对试图怀孕的不和谐夫妇没有用处。这显然是化学干预的替代方案……
Genital herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted diseases, 1 infecting approximately 20–30% of US adults. 2 Despite efforts to reduce HSV-2 transmission rates through behavioural modifications and chemical interventions, a 30% increase in seroprevalence was reported recently3 indicating the ongoing nature of this epidemic and the inadequacies of current therapeutic approaches. Primary HSV-2 infections produce vesiculoulcerative lesions and the establishment of a life-long latent infection in innervating sensory neurons. 4 Recurrent ulcerative lesions produced by viral reactivation predispose to human immunodeficiency virus type 1 (HIV-1) infection and colonization by other pathogens. 5, 6 Viral reactivation also results in asymptomatic viral shedding episodes that are a major factor in viral transmission. 7 The majority of HSV-2-seropositive people are unaware that they are infected and can transmit the virus in the absence of clinically apparent lesions further complicating control of infection. 7 Such asymptomatic viral shedding events occur as frequently as 40% of sampled days as measured by PCR. 5, 7 Effective therapeutic approaches ideally would not only minimize the severity and duration of primary and recurrent disease but also would reduce the shedding of virus from genital mucosa to lower transmission rates. Nobel Laureate Gertrude Elion and her colleagues introduced one of the most successful approaches for chemical intervention against HSV infections based upon the promiscuity of the viral thymidine kinase (TK) and its phosphorylation of nucleoside analogues. 8 Incorporation of the activated analogue terminates synthesis of the viral DNA genome. 8 Aciclovir, the lead compound from Elion’s work, is used widely; however, poor bioavailability requires high doses and inconvenient dosing schedules leading to poor compliance and treatment failures. Derivatives of aciclovir and other nucleoside analogues have been identified with better profiles, but also require multiple dosing regimens. More recently, chronic suppressive drug therapy (eg valaciclovir, 3–5 doses/day for life) has been reported to reduce inapparent viral shedding and possibly transmission. 9 When dosed appropriately, the current interventions modestly reduce lesion duration and viral shedding is reduced only with chronic suppressive therapy, indicating the need for improved or synergistic intervention strategies. Multiple high dose regimens and the specific targeting of a viral function like TK can be expected to select progeny with adaptive mutations resulting in antiviral resistance. As predicted, HSV-2 antiviral-resistant viruses are becoming more common especially in immunocompromised patients. 10 There is increasing interest in work evaluating methods for preventing transmission of HSV-2 and other genital pathogens through the use of topical microbicides. Such compounds act to block attachment or prevent entry of the virus to the host cell. 11 The ideal microbicide would be safe and efficacious, undetectable, inexpensive and have broad range efficacy against a variety of pathogens. Preclinical studies have indicated that these compounds are effective if given immediately before or just after pathogen exposure limiting convenient and covert application. A number of microbicide candidates are in clinical evaluation; however, at present, none have shown the level of efficacy against HSV-2 observed in animal models. Additionally, many of the microbicides under evaluation are contraceptive and therefore not useful for discordant couples attempting to conceive.An obvious alternative to chemical interventions …