In Vivo Evaluation of Safety and Toxicity of a Lactobacillus jensenii Producing Modified Cyanovirin-N in a Rhesus Macaque Vaginal Challenge Model
In Vivo Evaluation of Safety and Toxicity of a Lactobacillus jensenii Producing Modified Cyanovirin-N in a Rhesus Macaque Vaginal Challenge Model
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DOI：
10.1371/journal.pone.0078817
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发表时间：
2013-11-12
期刊：
影响因子：
3.7
通讯作者：
Hamer, Dean H.
中科院分区：
文献类型：
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作者：
Brichacek, Beda;Lagenaur, Laurel A.;Hamer, Dean H.
人类免疫缺陷病毒1型(HIV-1)在妇女宫颈阴道粘膜的性传播受到许多因素的影响，包括微生物区系和潜在炎症的存在。重要的是，潜在的艾滋病毒防治剂不会以一种促进艾滋病毒感染的方式改变粘膜环境。在恒河猴反复阴道猴HIV(SHIVSF162P3)攻击模型中，我们研究了“活”杀菌剂对阴道粘膜环境的影响。杀微生物剂中含有一种表达HIV-1进入抑制物的人阴道詹森乳杆菌，修饰的氰基韦林-N(MCV-N)，此后称为LB-MCV-N。在为期6周的研究期间，每周用LB-MCV-N在猕猴阴道内定植，并在定植后6天采集可培养细菌、pH和宫颈-阴道细胞因子的样本。我们发现，在SIV攻击期间，在其阴道微生物区系中保留了工程菌株LB-MCV-N的猕猴，在定植水平较高时，其pH值较低，并且没有炎性细胞因子的证据。事实上，IL-13是一种炎症介质，在Lb-MCV-N定植的猕猴中检测到的频率低于对照组，我们发现在SIV攻击期，在Lb-MCV-N定植的猕猴中，IL-1RA的水平更高。我们注意到粘膜IL-1RA水平与血浆病毒载量峰值之间呈负相关，因此，在用LB-MCV-N治疗的猕猴中，较高的IL-1RA与较低的病毒载量相关。这些数据支持使用LB-MCV-N作为一种安全的“活”杀菌剂，并表明乳杆菌本身可能对粘膜环境产生积极影响。
Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across the cervicovaginal mucosa in women is influenced by many factors including the microbiota and the presence of underlying inflammation. It is important that potential HIV preventative agents do not alter the mucosal environment in a way that enhances HIV acquisition. We examined the impact of a "live'' microbicide on the vaginal mucosal environment in a rhesus macaque repeated vaginal simian-HIV (SHIVSF162P3) challenge model. The microbicide contained a human vaginal Lactobacillus jensenii expressing the HIV-1 entry inhibitor, modified Cyanovirin-N (mCV-N), and henceforth called LB-mCV-N. Macaques were colonized vaginally each week with LB-mCV-N and sampled six days after colonization for culturable bacteria, pH and cervical-vaginal cytokines during the duration of the six-week study. We show that macaques that retained the engineered LB-mCV-N strain in their vaginal microbiota, during SHIV challenge, had lower pH, when colonization levels were higher, and had no evidence of inflammatory cytokines. Indeed, Interleukin-13, a mediator of inflammation, was detected less often in LB-mCV-N colonized macaques than in controls and we found higher levels of Interleukin 1 receptor antagonist (IL-1RA) in LB-mCV-N colonized macaques during the SHIV challenge period. We noted an inverse correlation between levels of mucosal IL-1RA and peak plasma viral load, thus higher IL-1RA correlated with lower viral load in LB-mCV-N treated macaques. These data support the use of LB-mCV-N as a safe "live'' microbicide and suggest that lactobacilli themselves may positively impact the mucosal environment.