Pathogenic Mechanisms in HIV Disease

用高效抗逆转录病毒疗法(HAART)治疗HIV感染对HIV患者有很大好处。不幸的是，它也与相当程度的副作用有关。在艾滋病毒患者的治疗中，悬而未决的问题包括开始治疗的最佳时间以及一旦开始治疗是否需要终生治疗。为了确定在有效治疗后在没有药物的情况下艾滋病毒水平是否会继续受到抑制，进行了一项研究，其中长期有效抑制病毒复制的患者停止了治疗。不幸的是，所有患者都表现出病毒复制的快速复发。病毒反弹水平最低的是那些在最初感染艾滋病毒后相对较短时间开始治疗的患者。在停止治疗后观察到的病毒复制的增加与CD4+T淋巴细胞水平的下降和CD4+T细胞周转率的增加有关。此外，仔细分析在HAART存在的情况下艾滋病毒复制持续高水平的患者，能够确定一种独特的突变，涉及艾滋病毒逆转录酶的67个氨基酸的缺失。缺失加上T69G突变导致了高水平的核苷耐药性，而不会损害艾滋病病毒的复制能力。在对艾滋病毒感染者免疫系统的研究中早期观察到，这些患者的外周血单核细胞对破伤风类毒素等远程回忆抗原刺激的反应能力存在严重缺陷。这些研究表明，在进行性HIV感染的背景下看到的CD4下降与T细胞受体(TCR)的进行性倾斜有关。在CD4T细胞池整体大小显著减少的情况下，TCR的这种倾斜程度表明，在缺乏大量干细胞分化的情况下，T细胞库中的一些元素可能会永久性地丢失。为了确定在抗逆转录病毒治疗的背景下看到的CD4T细胞库的增加是否代表免疫系统的完全或仅部分恢复，进行了一项研究，其中有不同程度的CD4T细胞恢复的患者被新抗原噬菌体phiX174免疫。与健康对照组相比，接受艾滋病毒感染治疗的患者对新抗原的免疫反应明显减少。这些数据表明，在HIV感染患者中较早发现缺乏抗原特异性反应的原因很可能是抗原特异性克隆的数量减少到特定的临界水平以下。

Treatment of HIV infection with highly active antiretroviral therapy (HAART) has been of great benefit to patients with HIV disease. Unfortunately it is also associated with a considerable degree of side effects. Among the unanswered questions in the treatment of patients with HIV are the questions of the best time to start therapy and whether or not therapy needs to be life ?long once it is started. To determine whether or not levels of HIV would remain suppressed in the absence of drug following effective therapy a study was carried out in which patients with long-term effective suppression of viral replication had their therapy stopped. Unfortunately, all patients showed a rapid recurrence of viral replication. The lowest levels of viral rebound were in those patients in whom therapy had been started relatively soon following primary HIV infection. The increases in viral replication that were observed following the discontinuation of therapy were associated with decreases in the levels of CD4+ T lymphocytes and increases in the rate of CD4+ T cell turnover. In addition, careful analysis of patients with ongoing high levels of HIV replication in the presence of HAART was able to identify a unique mutation involving the deletion of amino acid 67 of the HIV reverse transcriptase of HIV. The deletion in combination with a T69G mutation led to high level nucleoside resistance without compromise of the ability of the AIDS virus to replicate. An early observation in studies of the immune systems of patients with HIV infection was that these patients had a profound defect in the ability of their peripheral blood mononuclear cells to respond to stimulation with remote recall antigens such as tetanus toxoid. These studies suggested that the CD4 declines seen in the setting of progressive HIV infection were associated with a progressive skewing of the T cell receptor (TCR). This degree of TCR skewing in the setting of a marked decrease in the overall size of the CD4 T cell pool suggests that some elements of the T cell repertoire may be permanently lost in the absence of significant amounts of stem cell differentiation. To determine whether or not the increases in the CD4 T cell pool seen in the context of antiretroviral therapy represents a complete or only partial restoration of the immune system, a study was undertaken in which patients with varying degrees of CD4 T cell recovery were immunized with the neoantigen bacteriophage PhiX174. Immune responses to the neoantigen were significantly less in the patients with treated HIV infection compared to healthy controls. These data suggest that the earlier finding of lack of antigen-specific responses in patients with HIV infection are most likely due to a decrease in the number of antigen-specific clones below a certain critical level.