Envelope-Modified Single-Cycle Simian Immunodeficiency Virus Selectively Enhances Antibody Responses and Partially Protects against Repeated, Low-Dose Vaginal Challenge
Envelope-Modified Single-Cycle Simian Immunodeficiency Virus Selectively Enhances Antibody Responses and Partially Protects against Repeated, Low-Dose Vaginal Challenge
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DOI：
10.1128/jvi.00945-10
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发表时间：
2010-10-01
影响因子：
5.4
通讯作者：
Evans, David T.
中科院分区：
文献类型：
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作者：
Alpert, Michael D.;Rahmberg, Andrew R.;Evans, David T.
用仅限于一个感染周期的猿猴免疫缺陷病毒 (SIV) 株对恒河猴进行免疫，可引发 T 细胞对多种病毒基因产物和抗体的反应，这些产物和抗体能够中和实验室适应的 SIV，但不能中和 SIV 的初级分离株。为了改善抗体反应，我们用三种单周期 SIV (scSIV) 菌株对恒河猴进行了免疫接种，这些菌株表达的包膜糖蛋白经过修饰，缺乏被认为会干扰中和抗体产生的结构特征。这些经过包膜修饰的 scSIV 菌株缺乏 gp120 中的 5 个潜在的 N 连接糖基化位点、gp41 中的 3 个潜在的 N 连接糖基化位点或 gp120 的 V1V2 区域中的 100 个氨基酸。在第 0、6 和 12 周施用了由三种包膜修饰的 scSIV 菌株的混合物组成的三剂疫苗，然后在第 18 周和第 24 周注射了两次水泡性口炎病毒 (VSV) G 反式互补的 scSIV 加强接种。尽管这种免疫方案没有引发能够可检测地中和 SIV(mac)239 或 SIV(mac)251(UCD)，针对包膜修饰菌株的中和抗体滴度选择性增强。在阴道粘膜中观察到病毒特异性抗体和T细胞。经过 20 周的重复、低剂量 SIV(mac)251(UCD) 阴道攻击后，八只免疫动物中有六只被感染，而六只初始对照动物中有六只被感染。尽管免疫并没有显着降低获得免疫缺陷病毒感染的可能性，但相对于未接触过的对照动物，在免疫动物中观察到峰值和设定点病毒载量在统计学上显着降低。
Immunization of rhesus macaques with strains of simian immunodeficiency virus (SIV) that are limited to a single cycle of infection elicits T-cell responses to multiple viral gene products and antibodies capable of neutralizing lab-adapted SIV, but not neutralization-resistant primary isolates of SIV. In an effort to improve upon the antibody responses, we immunized rhesus macaques with three strains of single-cycle SIV (scSIV) that express envelope glycoproteins modified to lack structural features thought to interfere with the development of neutralizing antibodies. These envelope-modified strains of scSIV lacked either five potential N-linked glycosylation sites in gp120, three potential N-linked glycosylation sites in gp41, or 100 amino acids in the V1V2 region of gp120. Three doses consisting of a mixture of the three envelope-modified strains of scSIV were administered on weeks 0, 6, and 12, followed by two booster inoculations with vesicular stomatitis virus (VSV) G trans-complemented scSIV on weeks 18 and 24. Although this immunization regimen did not elicit antibodies capable of detectably neutralizing SIV(mac)239 or SIV(mac)251(UCD), neutralizing antibody titers to the envelope-modified strains were selectively enhanced. Virus-specific antibodies and T cells were observed in the vaginal mucosa. After 20 weeks of repeated, low-dose vaginal challenge with SIV(mac)251(UCD), six of eight immunized animals versus six of six naive controls became infected. Although immunization did not significantly reduce the likelihood of acquiring immunodeficiency virus infection, statistically significant reductions in peak and set point viral loads were observed in the immunized animals relative to the naive control animals.