Papillomavirus Virion Proteins and Vaccines

乳头瘤病毒（PV）感染动物和人的上皮细胞，在那里它们通常被感染。 在感染部位诱发良性增生（疣或湿疣）。然而，病变 由人乳头瘤病毒（HPV）的一个子集，特别是HPV 16诱导的肿瘤， 这些HPV导致宫颈癌和其他几种上皮恶性肿瘤。 我们目前的研究主要涉及疫苗和其他感染的发展。 针对HPV的抑制策略和HPV生命周期的阐明。我们之前 开发了一种产生高滴度传染性乳头瘤病毒的有效策略， 带有标记质粒的颗粒，称为假病毒。假病毒 感染模仿HPV感染的早期步骤，因此可以用于研究这些感染。 事件以及可能抑制它们的干预措施。我们的体内研究也表明， 假病毒废除了真正HPV的严格种属特异性，同时保留了它们的 向上皮性这些特性使我们能够开发出第一个宫颈阴道挑战 HPV的模型。该系统允许在体内探索在建立免疫应答中所涉及的步骤。 感染我们已经发现，雌性小鼠生殖道的感染，甚至 单层宫颈内细胞，需要病毒与基底膜（BM）结合， 这只能发生在足以暴露于骨髓的微创伤之后。病毒粒子结合到 乙酰肝素酶治疗阻止了BM中的乙酰肝素硫酸化蛋白聚糖， 感染BM结合的病毒经历酶介导的构象变化， 导致L2次要衣壳蛋白中的表位暴露。成功感染 上皮细胞仅发生BM相关变化后。正在进行的实验是 利用体内系统研究目前HPV疫苗预防的机制， 并帮助开发第二代HPV疫苗。协同 约翰霍普金斯大学的同事，我们发现一种候选的基于L2的疫苗可能具有 作为泛HPV疫苗的潜力，因为它可以诱导广泛的HPV中和。

Papillomaviruses (PVs) infect the epithelia of animals and man, where they generally induce benign proliferation (warts or condylomata) at the site of infection. However, lesions induced by a subset of human papillomaviruses (HPVs), especially HPV16, can undergo malignant progression, and these HPVs cause cervical cancer and several other epithelial malignancies. Our current research is primarily concerned with development of vaccines and other infection inhibition strategies against HPV and elucidation of the HPV life cycle. We previously developed an efficient strategy for generating high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids, designated pseudoviruses. Pseudovirus infection mimics the early steps in HPV infection and can therefore be used to study these events as well as interventions that may inhibit them. Our in vivo studies have also shown the pseudoviruses abrogate the strict species-specificity of authentic HPVs while retaining their epitheliotropism. These properties enabled us to develop the first cervicovaginal challenge model for HPVs. This system permits in vivo exploration of the steps involved in establishing infection. We have found that the infection of the female mouse genital tract, even of monolayer endocervical cells, requires binding of the virus to the basement membrane (BM), which can only occur following microtrauma sufficient to expose to the BM. The virions bind to heparan sulfated proteoglycans in the BM, as heparanase treatment prevents both BM binding and infection. The BM-bound virus undergoes an enzymatically mediated conformational change, leading to exposure of an epitope in the L2 minor capsid protein. Successful infection of epithelial cells only occurs after the BM-associated changes. Ongoing experiments are utilizing the in vivo system to study the mechanisms by which the current HPV vaccine prevents infection as well as to help develop second generation HPV vaccines. In collaboration with colleagues at Johns Hopkins, we have found that a candidate L2-based vaccine may have potential as a pan-HPV vaccine, as it can induce neutralization of a broad range of HPVs.