A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.
A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.
复制标题
DOI：
10.1371/journal.pone.0135288
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mohapatra SS
中科院分区：
文献类型：
--
作者：
Boyapalle S;Xu W;Raulji P;Mohapatra S;Mohapatra SS
人类免疫缺陷病毒（HIV） 1型和2型（HIV-1和HIV-2）是艾滋病的病原。全世界大多数艾滋病毒-1感染者是妇女，她们在性接触中感染艾滋病毒。阻断艾滋病毒在女性下生殖道的粘膜传播和局部传播对于预防感染和最终消除大流行非常重要。杀微生物剂的作用是消灭微生物或防止它们引起感染。因此，许多不同类型的杀微生物剂正在研究中，然而，它们的溶解度和生物利用度的缺乏以及毒性一直是主要障碍。在此，我们报道了多功能壳聚糖-脂质纳米复合物的发展，该复合物可以有效地递送编码siRNA的质粒作为杀微生物剂而没有副作用，并且在体外和体内模型中都提供了显著的抗HIV保护。将壳聚糖或壳聚糖-脂质（ch脂质）与编码hiv -1特异性sirna （psirna）的质粒复合物在HEK-293细胞、非人灵长类动物PBMCs、三维人阴道外宫颈组织（3D-VEC）模型和非人灵长类动物模型中的效果进行了评价。此外，在非人类灵长类动物模型中，预防性地给予脂质以阴道内递送psiRNA鸡尾酒膏，结果显示SHIV（猿猴/人类免疫缺陷病毒SF162）病毒滴度大幅降低。综上所述，这些研究证明了脂质- sirna纳米复合物作为抗HIV感染的潜在基因杀微生物剂的潜力。
Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections.