Kinetics of lymphocyte proliferation during primary immune response in macaques infected with pathogenic simian immunodeficiency virus SIVmac251:: Preliminary report of the effect of early antiviral therapy
Kinetics of lymphocyte proliferation during primary immune response in macaques infected with pathogenic simian immunodeficiency virus SIVmac251:: Preliminary report of the effect of early antiviral therapy
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DOI：
10.1128/jvi.77.23.12479-12493.2003
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发表时间：
2003-12-01
影响因子：
5.4
通讯作者：
Vaslin, B
中科院分区：
文献类型：
--
作者：
Benlhassan-Chahour, K;Penit, C;Vaslin, B
本研究的目的是评估淋巴细胞增殖的动力学与致病性猴免疫缺陷病毒（SIV）的猕猴原发感染，并研究短期的高活性抗逆转录病毒治疗（HAART）预防的影响。通过静脉途径用SIVmac 251感染12只猕猴，并从感染后4小时开始给予治疗28天。第1组接受安慰剂，第2组和第3组接受齐多夫定（AZT）、拉米夫定（3 TC）和茚地那韦的联合治疗。第2组猕猴每天两次口服AZT（4.5 mg/kg体重）、3 TC（2.5 mg/kg）和茚地那韦（20 mg/kg），而第3组猕猴每天两次皮下注射AZT（4.5 mg/kg）和3 TC（2.5 mg/kg），以改善这些药物的药代动力学作用，并给予更高剂量的茚地那韦（60 mg/kg）。通过监测离体5-溴-2 '-脱氧尿苷（BrdU）摄取和荧光激活细胞分选分析来分析淋巴细胞增殖的动力学。HAART不能预防SIV感染，但对病毒载量有很大影响：第2组在抗病毒治疗期间病毒血症延迟并降低，治疗停止后控制更好，第3组在治疗期间病毒血症维持在较低水平，一些猕猴的血液中甚至检测不到病毒，但没有证据表明治疗后病毒控制有所改善。我们提供的直接证据表明，分裂的NK细胞比血液中分裂的T细胞（主要是CD 45 RA（-）T细胞）更早被检测到，反映了血浆病毒血症。分裂的CD 8（+）T细胞比分裂的CD 4（+）T细胞更早被检测到，增殖T细胞的最高百分比与部分控制峰值病毒血症的第一个证据和循环γ干扰素阳性CD 8（+）T细胞的百分比增加相一致。SIV初次感染期间血液中的细胞增殖水平明显与病毒复制水平相关，因为通过暴露后HAART抑制病毒复制强烈降低了淋巴细胞增殖。本研究的结果和结论是基于少量动物的实验，因此是初步的。
The aim of this study was to evaluate the kinetics of lymphocyte proliferation during primary infection of macaques with pathogenic simian immunodeficiency virus (SIV) and to study the impact of short-term postexposure highly active antiretroviral therapy (HAART) prophylaxis. Twelve macaques were infected by intravenous route with SIVmac251 and given treatment for 28 days starting 4 h postexposure. Group 1 received a placebo, and groups 2 and 3 received combinations of zidovudine (AZT), lamivudine (3TC), and indinavir. Macaques in group 2 received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route whereas macaques in group 3 were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs, and a higher dose of indinavir (60 mg/kg). The kinetics of lymphocyte proliferation were analyzed by monitoring 5-bromo-2'-deoxyuridine (BrdU) uptake ex vivo and by fluorescence-activated cell sorting analysis. HAART did not protect against SIV infection but did strongly impact on virus loads: viremia was delayed and lowered during antiviral therapy in group 2, with better control after treatment was stopped, and in group 3, viremia was maintained at lower levels during treatment, with virus even undetectable in the blood of some macaques, but there was no evidence of improved control of the virus after treatment. We provide direct evidence that dividing NK cells are detected earlier than dividing T cells in the blood (mostly in CD45RA(-) T cells), mirroring plasma viremia. Dividing CD8(+) T cells were detected earlier than dividing CD4(+) T cells, and the highest percentages of proliferating T cells coincided with the first evidence of partial control of peak viremia and with an increase in the percentage of circulating gamma interferon-positive CD8(+) T cells. The level of cell proliferation in the blood during SIV primary infection was clearly associated with viral replication levels because the inhibition of viral replication by postexposure HAART strongly reduced lymphocyte proliferation. The results and conclusions in this study are based on experiments in a small numbers of animals and are thus preliminary.