ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge.
ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge.
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DOI：
10.1371/journal.ppat.1002890
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Evans DT
中科院分区：
文献类型：
--
作者：
Alpert MD;Harvey JD;Lauer WA;Reeves RK;Piatak M Jr;Carville A;Mansfield KG;Lifson JD;Li W;Desrosiers RC;Johnson RP;Evans DT
猿猴免疫缺陷病毒 (SIV) 减毒活毒株通常赋予恒河猴明显的针对致病性 SIV 攻击的绝育免疫力。了解减毒活 SIV 的保护机制可能为了解 HIV-1 所需的免疫反应提供重要见解。在这里，我们研究了针对中和抗性 SIV 攻击株的抗体的开发，并测试了这些抗体与保护相关的假设。在没有可检测到的中和抗体的情况下，接种 SIVΔnef 三周后，Env 特异性抗体依赖性细胞介导的细胞毒性 (ADCC) 出现，并随着时间的推移逐渐增加，并且与 SIVΔnef 复制成正比。与使用仅限于单个感染周期的非持续性 SIV 菌株免疫相比，SIVΔnef 持续感染引起显着更高的 ADCC 滴度。 ADCC 滴度针对与 Env 疫苗株相匹配的病毒，但针对表达异源 Env 蛋白的病毒可测量。在两个独立的实验中，利用菌株特异性或免疫的时间依赖性成熟来克服针对 SIVmac251 攻击的完全保护，在未感染的 SIVΔnef 接种的猕猴中，ADCC 活性的测量值高于感染的猕猴。这些观察结果表明，SIVΔnef 引发的抗体反应的特征与减毒活 SIV 的保护标志一致，并揭示了指导 ADCC 的 Env 特异性抗体与 SIVΔnef 的明显灭菌保护之间的关联。减毒活疫苗可以预防恒河猴实验攻击后的猿猴免疫缺陷病毒（SIV）感染。尽管出于安全考虑，人们无法给人类接种减毒活 HIV-1 疫苗，但通过替代方法复制减毒活 SIV 诱导的免疫类型还是有可能的。因此，识别减毒活 SIV 保护的免疫反应并了解其诱导将为 HIV-1 疫苗设计提供指导。病毒特异性抗体反应成熟的重要作用可以解释减毒活 SIV 保护作用的时间依赖性发展。然而，阻止攻击病毒进入细胞的抗体通常是检测不到的。抗体还可以通过抗体依赖性细胞介导的细胞毒性（ADCC）直接杀死病毒感染的细胞。在这里，我们证明减毒活 SIV 会随着时间的推移诱导 ADCC 逐渐增加，并且这些抗体的产生依赖于疫苗株的持续复制。在两个不同的实验中，用减毒活 SIV 免疫的动物在致病性 SIV 攻击后仍未感染，其 ADCC 测量值高于感染的动物。我们的结果表明，抗体有助于减毒活 SIV 的保护，并且持续刺激抗体反应可能对于 HIV-1 疫苗诱导高 ADCC 活性至关重要。
Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVΔnef, increased progressively over time, and was proportional to SIVΔnef replication. Persistent infection with SIVΔnef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIVmac251 challenge, measures of ADCC activity were higher among the SIVΔnef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVΔnef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVΔnef. Live-attenuated vaccines can prevent simian immunodeficiency virus (SIV) infection upon experimental challenge of rhesus macaques. Although safety considerations preclude vaccinating humans with live-attenuated HIV-1, it may be possible to replicate the types of immunity induced by live-attenuated SIV through an alternative approach. Thus, identifying the immune responses underlying protection by live-attenuated SIV and understanding their induction would provide guidance for HIV-1 vaccine design. An important role for the maturation of virus-specific antibody responses could explain the time-dependent development of protection by live-attenuated SIV. However, antibodies that block the entry of the challenge virus into cells are usually undetectable. Antibodies can also direct the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Here we show that live-attenuated SIV induces progressive increases in ADCC over time, and that the development of these antibodies is dependent upon the persistent replication of the vaccine strain. In two different experiments, the animals immunized with live-attenuated SIV that remained uninfected after pathogenic SIV challenge had higher measures of ADCC than those that became infected. Our results suggest that antibodies contribute to protection by live-attenuated SIV, and that persistent stimulation of antibody responses may be essential for HIV-1 vaccines to induce high ADCC activity.
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影响因子：
64.5
作者：
BEREK, C;BERGER, A;APEL, M
通讯作者：
APEL, M
影响因子：
5.4
作者：
Alpert, Michael D.;Rahmberg, Andrew R.;Evans, David T.
通讯作者：
Evans, David T.
DOI：
10.1084/jem.20060134
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gauduin MC;Yu Y;Barabasz A;Carville A;Piatak M;Lifson JD;Desrosiers RC;Johnson RP
通讯作者：
Johnson RP
HIV-1 疫苗功效试验的免疫相关分析。
DOI：
10.1056/nejmoa1113425
发表时间：
2012-04-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Haynes BF;Gilbert PB;McElrath MJ;Zolla-Pazner S;Tomaras GD;Alam SM;Evans DT;Montefiori DC;Karnasuta C;Sutthent R;Liao HX;DeVico AL;Lewis GK;Williams C;Pinter A;Fong Y;Janes H;DeCamp A;Huang Y;Rao M;Billings E;Karasavvas N;Robb ML;Ngauy V;de Souza MS;Paris R;Ferrari G;Bailer RT;Soderberg KA;Andrews C;Berman PW;Frahm N;De Rosa SC;Alpert MD;Yates NL;Shen X;Koup RA;Pitisuttithum P;Kaewkungwal J;Nitayaphan S;Rerks-Ngarm S;Michael NL;Kim JH
通讯作者：
Kim JH
DOI：
10.1086/655654
发表时间：
2010-10-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Alter G;Moody MA
通讯作者：
Moody MA