Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates
Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: a model for the evaluation of vaccine efficacy in nonhuman primates
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DOI：
10.1128/jvi.78.6.3140-3144.2004
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发表时间：
2004-03-01
影响因子：
5.4
通讯作者：
Watkins, DI
中科院分区：
文献类型：
--
作者：
McDermott, AB;Mitchen, J;Watkins, DI
猴免疫缺陷病毒（SIV）对恒河猴的攻击为人类免疫缺陷病毒（HIV）疫苗策略的评估提供了相关模型。为了确保所有猕猴都受到感染，疫苗接种者和对照者暴露于大剂量的致病性SIV。这些非生理性的高剂量挑战可能会压倒潜在有效的疫苗反应，从而对疫苗评估产生不利影响。为了确定更生理相关的低剂量攻毒是否能在印度恒河猴中引发感染并导致疾病，我们采用了重复低剂量攻毒策略，旨在将病毒接种量减少到更生理相关的剂量。为了更接近地模拟HIV的攻击，我们将致病性SIVmac239分别以30、300和3000 50%组织培养感染剂量（TCID50）对三组6只动物进行粘膜重复攻击。通过敏感的定量逆转录- pcr评估感染情况，在30、300和3000 TCID50组中，感染次数分别为平均8次、5.5次和1次。无论攻击剂量如何，6只动物中有5只的死亡率、体液免疫反应和峰值血浆病毒动力学相似。有趣的是，通过ELISPOT测定，低剂量SIVmac239攻击的猕猴产生了广泛的t细胞免疫反应。这种低剂量重复激发可能是评估潜在疫苗方案的一个有价值的工具，并为致病性SIVmac239激发实验提供了一种更具生理学相关性的方案。
Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides a relevant model for the assessment of human immunodeficiency virus (HIV) vaccine strategies. To ensure that all macaques become infected, the vaccinees and controls are exposed to large doses of pathogenic SIV. These nonphysiological high-dose challenges may adversely affect vaccine evaluation by overwhelming potentially efficacious vaccine responses. To determine whether a more physiologically relevant low-dose challenge can initiate infection and cause disease in Indian rhesus macaques, we used a repeated low-dose challenge strategy designed to reduce the viral inoculum to more physiologically relevant doses. In an attempt to more closely mimic challenge with HIV, we administered repeated mucosal challenges with 30, 300, and 3,000 50% tissue culture infective doses (TCID50) of pathogenic SIVmac239 to six animals in three groups. Infection was assessed by sensitive quantitative reverse transcription-PCR and was achieved following a mean of 8, 5.5, and 1 challenge(s) in the 30, 300, and 3,000 TCID50 groups, respectively. Mortality, humoral immune responses, and peak plasma viral kinetics were similar in five of six animals, regardless of challenge dose. Interestingly, macaques challenged with lower doses of SIVmac239 developed broad T-cell immune responses as assessed by ELISPOT assay. This low-dose repeated challenge may be a valuable tool in the evaluation of potential vaccine regimes and offers a more physiologically relevant regimen for pathogenic SIVmac239 challenge experiments.