Passive immune globulin therapy in the SIV/macaque model: Early intervention can alter disease profile
Passive immune globulin therapy in the SIV/macaque model: Early intervention can alter disease profile
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DOI：
10.1016/0165-2478(96)02563-1
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发表时间：
1996-06-01
影响因子：
4.4
通讯作者：
Johnson, PR
中科院分区：
文献类型：
--
作者：
Haigwood, NL;Watson, A;Johnson, PR
艾滋病的主要问题之一是宿主免疫系统和病毒在感染动态和感染者艾滋病发展中所发挥的作用。为了测试抗体在控制病毒感染中的作用，在感染早期将高剂量的SIV免疫球蛋白被动转移到受感染的猕猴体内。在感染后 1 天和 14 天，将从 SIV 感染的长期无进展猕猴 (SIVIG) 血浆中纯化的免疫球蛋白或正常免疫球蛋白池 (正常 Ig) 注入 SIVsmE660 感染的猕猴 (170 mg/kg)。监测动物的 SIV 特异性抗体、病毒血症、血浆抗原血症和临床病程。所有动物均感染了SIV。感染后16个月；联合对照组中的五只猕猴已被安乐死，其中一只在感染后 20 周时病情迅速恶化，病情严重恶化。对照组的四只猕猴有艾滋病迹象，并伴有高水平且不断增加的病毒和 p27 抗原血症。十只对照动物中的一只在所有测试时间中血浆、外周血和淋巴结单核细胞中的病毒载量非常低，并且一直保持无病状态。在 SIVIG 治疗组中，两只猕猴在 18-20 周时因艾滋病（疾病快速进展）而被安乐死。 SIVIG 组中的三只猕猴的血浆、外周血单核细胞 (PBMC) 和淋巴结单核细胞 (LNMC) 中的病毒水平最初很高，在感染后 6 周时降至基线，并在 16 个月内保持非常低的水平或呈阴性，迄今为止，在该模型中未经治疗的动物中尚未观察到这种疾病特征。这些猕猴在临床上仍然保持健康。第六只接受治疗的动物也很健康，病毒负荷非常低，只能通过巢式聚合酶链反应 (PCR) 检测到。所有接受 SIVIG 治疗的猕猴在感染的前 10 周内都没有出现令人愉悦的 p27 血浆抗原血症，这表明 IgG 有效地与病毒复合。接受治疗的动物中的免疫相关性包括从头病毒特异性抗体和/或细胞毒性T细胞（CTL）的发展，这两者都是长期非进展者的标志。两只经 SIVIG 治疗后迅速发展为疾病的猕猴没有可检测到的从头体液免疫反应，这在人类快速艾滋病毒疾病中常见。单独的包膜特异性抗体和病毒中和抗体不足以阻止疾病进展，因为非进展者和进展者的血浆都具有高滴度的针对 SIVsmE660 的包膜特异性抗体和中和抗体。临床预后不良与血浆、PBMC 和淋巴结中病毒载量中度至高且不断增加有关。良好的临床预后与外周血和淋巴结中低或不可检测的急性后病毒血症相关。我们假设 SIVIG 在感染的前 4 至 8 周内通过免疫复合物消除或减少血浆病毒，然后维持这种低水平的病毒血症，直到宿主免疫反应能够控制病毒，从而减少病毒的传播。通过被动 IgG 减少感染早期的病毒负荷可以改变猕猴 SIV 感染的疾病结果。对该策略的修改可能会导致人类 HIV-1 感染的有效早期治疗。
One of the major questions in AIDS is the role that the host immune system and the virus play in the dynamics of infection and the development of AIDS in an infected individual. In order to test the role of antibody in controlling viral infection, high-dose SIV-immune globulin was passively transferred to infected macaques early in infection. Immune globulin purified from the plasma of an SIV-infected long-term non-progressor macaque (SIVIG) or a pool of normal immune globulin (normal Ig) was infused into SIVsmE660-infected macaques (170 mg/kg) at one and fourteen days post infection. Animals were monitored for SIV-specific antibodies, viremia, plasma antigenemia, and clinical course. All animals were infected by SIV. At 16 months post infection; five macaques in the combined control groups have been euthanized,one as a rapid progressor with debilitating disease at 20 weeks post infection. Four macaques from the comparison groups have signs of AIDS, accompanied by high and increasing levels of virus and p27 antigenemia. One of the ten control animals had a very low virus load in plasma and peripheral blood and lymph node mononuclear cells at all times tested and has remained disease-free. In the SIVIG treatment group, two macaques were euthanized at 18-20 weeks due to AIDS, rapid progressors to disease. Three macaques in the SIVIG group had an initial high level of virus in plasma, peripheral blood mononuclear cells (PBMC), and lymph node mononuclear cells (LNMC), which dropped to baseline at 6 weeks post infection and has remained very low or negative for 16 months, a disease profile which has not been observed in untreated animals in this model to date. These macaques have remained clinically healthy. The sixth treated animal is also healthy, with very low virus burden that is detectable only by nested set polymerase chain reaction (PCR). All SIVIG-treated macaques had no delectable p27 plasma antigenemia for the first 10 weeks of infection, demonstrating that the IgG effectively complexed with the virus. The immunological correlates in the treated animals include development of de novo virus-specific antibodies and/or cytotoxic T cell (CTL), both of which are hallmarks of long term non-progressors. The two SIVIG-treated macaques that progress to disease rapidly had no detectable de novo humoral immune responses, as is often seen in rapid HIV disease in humans. Envelope-specific and virus neutralizing antibodies alone were not sufficient to prevent disease progression, as the plasma of both non-progressors as well as progressors had high titers of envelope-specific and neutralizing antibodies against SIVsmE660. Poor clinical prognosis was associated with moderate to high and increasing virus loads in plasma, PBMC, and lymph nodes. Good clinical prognosis correlated with low or undetectable post acute viremia in the peripheral blood and lymph nodes. We hypothesize that SIVIG reduced the spread of virus by eliminating or reducing plasma virus through immune complexes during the first four to 8 weeks of infection and then maintaining this low level of viremia until the host immune response was capable of virus control. Reduction of virus burden early in infection by passive IgG can alter disease outcome in SIV infection of macaques. Modifications of this strategy may lead to effective early treatment of HIV-1 infection in humans.