Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4
Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4
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DOI：
10.1073/pnas.1934747100
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发表时间：
2003-09-30
影响因子：
11.1
通讯作者：
Lee, PP
中科院分区：
文献类型：
--
作者：
Chang, TLY;Chang, CH;Lee, PP
世界范围内艾滋病毒的主要传播方式是通过异性接触，宫颈-阴道粘膜是妇女进入的主要门户。宫颈-阴道粘膜自然地被共生细菌定植，主要是乳杆菌。为了解决女性控制的方法来阻断艾滋病毒异性传播的迫切需要，我们已经改造了自然的人类阴道詹森乳杆菌分离株，使其分泌双域CD4(2D CD4)蛋白。分泌的2D CD4识别构象依赖的抗CD4抗体，并与HIV-1 gp120结合，表明表达的蛋白采用天然构象。利用携带荧光素酶报告基因的HIV-1(HXB2)进行的单周期感染分析表明，乳杆菌来源的2D CD4以剂量依赖的方式抑制HIV-1进入靶细胞。重要的是，工程菌与重组HIV-1(HxB2)共孵育。报告病毒导致表达CD4-CXCR4-CCR5的HeLa细胞的病毒感染力显著降低。工程乳酸菌还导致主要分离株HIV-1(JR-FL)的传染性略有下降，但在统计上有显著意义。这代表着朝着在阴道微生物群中开发工程共生细菌以抑制艾滋病毒的异性传播迈出了重要的第一步。
The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervico-vaginal mucosa being the main portal of entry in women. The cervico-vaginal mucosa is naturally colonized with commensal bacteria, primarily lactobacilli. To address the urgent need for female-controlled approaches to block the heterosexual transmission of HIV, we have engineered natural human vaginal isolates of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins. The secreted 2D CD4 recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120, suggesting that the expressed proteins adopted a native conformation. Single-cycle infection assays using HIV-1(HXB2) carrying a luciferase reporter gene demonstrated that Lactobacillus-derived 2D CD4 inhibited HIV-1 entry into target cells in a dose-dependent manner. Importantly, coincubation of the engineered bacteria with recombinant HIV-1(HxB2). reporter virus led to a significant decrease in virus infectivity of HeLa cells expressing CD4-CXCR4-CCR5. Engineered lactobacilli also caused a modest, but statistically significant, decrease in infectivity of a primary isolate, HIV-1(JR-FL). This represents an important first step toward the development of engineered commensal bacteria within the vaginal microflora to inhibit heterosexual transmission of HIV.