Development of broad neutralization activity in simian/human immunodeficiency virus-infected rhesus macaques after long-term infection
Development of broad neutralization activity in simian/human immunodeficiency virus-infected rhesus macaques after long-term infection
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长期感染猿/人类免疫缺陷病毒感染的恒河猴后产生广泛的中和活性
DOI：
10.1097/qad.0000000000001724
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发表时间：
2018-03-13
期刊：
影响因子：
3.8
通讯作者：
Gao, Feng
中科院分区：
文献类型：
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作者：
Gao, Nan;Wang, Wei;Gao, Feng
目的：非人灵长类动物（NHP）是唯一可用于评估HIV-1包膜疫苗保护效果的动物模型。然而，在感染猿/人类免疫缺陷病毒（SHIV）的 NHP 中是否可以引发广泛中和抗体（bnAbs）尚未完全清楚。本研究的目的是调查感染 SHIV 的猕猴在长期感染后是否会像人类一样产生广泛的中和活性。设计：通过分析一组 2 级病毒及其突变体，确定感染 SHIV 的猕猴血浆中的中和广度和特异性。方法：对 44 只感染 SHIV1157ipd3N4、SHIVSF162P3 或 SHIVCHN19P4 的中国猕猴进行为期 54-321 周的随访。使用来自 19 只猕猴的存档血浆来确定针对 17 种 2 级包膜假病毒的中和广度和特异性。结果：三只 SHIVSF162P3 感染的猕猴和三只 SHIV1157ipd3N4 感染的猕猴的纵向血浆在感染后 1 年内很少中和病毒（<25%）。两只 SHIV1157ipd3N4 感染的猕猴的中和广度在第 6 年显着增加（≥65%）。六只感染 SHIV1157ipd3N4 的猕猴中的四只可以中和 50-75% 的病毒，而感染 SHIVSF162P3 或 SHIVCHN19P4 的猕猴在感染 6 年后都不能中和超过 25% 的病毒（P = 0.035）。中和特异性分析显示，V2、V3 或 CD4bs 区域中对 bnAb 具有抗性的突变可以消除来自三只 SHIV1157ipd3N4 感染的猕猴的 6 岁血浆的中和作用。结论：这些结果表明，在感染 SHIV1157ipd3N4 的猕猴中，与人类一样，在感染 4-6 年后，可以诱导出针对常见 HIV-1 表位的 bnAb，并且 SHIV/NHP 可以作为研究 bnAb 成熟的理想模型。
Objective: Nonhuman primates (NHPs) are the only animal model that can be used to evaluate protection efficacy of HIV-1 envelope vaccines. However, whether broadly neutralizing antibodies (bnAbs) can be elicited in NHPs infected with simian/human immunodeficiency virus (SHIV) has not been fully understood. The objective of this study is to investigate whether broad neutralization activities were developed in SHIV-infected macaques after long-term infection as in humans. Design: Neutralization breadth and specificities in plasmas from SHIV-infected macaques were determined by analyzing a panel of tier 2 viruses and their mutants. Methods: Forty-four Chinese macaques infected with SHIV1157ipd3N4, SHIVSF162P3 or SHIVCHN19P4 were followed for 54–321 weeks. Archived plasmas from 19 macaques were used to determine neutralization breadth and specificities against 17 tier 2 envelope-pseudoviruses. Results: Longitudinal plasma from three SHIVSF162P3-infected macaques and three SHIV1157ipd3N4-infected macaques rarely neutralized viruses (<25%) within 1 year of infection. The neutralization breadth in two SHIV1157ipd3N4-infected macaques significantly increased (≥65%) by year 6. Four of six SHIV1157ipd3N4-infected macaques could neutralize 50–75% viruses, whereas none of macaques infected with SHIVSF162P3 or SHIVCHN19P4 could neutralize more than 25% of viruses after 6 years of infection (P = 0.035). Neutralization specificity analysis showed mutations resistant to bnAbs in V2, V3 or CD4bs regions could abrogate neutralization by year-6 plasma from three SHIV1157ipd3N4-infected macaques. Conclusion: These results demonstrate that bnAbs targeting common HIV-1 epitopes can be elicited in SHIV1157ipd3N4-infected macaques as in humans after 4–6 years of infection, and SHIV/NHP can serve as an ideal model to study bnAb maturation.