Ansari Aftab A
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 2309 WMB, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Autoimmun Rev. 2004 Nov;3(7-8):530-40. doi: 10.1016/j.autrev.2004.07.009.
Autoimmune antibodies and autoimmune responses have been characterized in both human HIV infection and the rhesus macaque (RM) non-human primate model of SIV infection and reasoned to contribute to the pathogenesis of AIDS. Many theories for the induction and maintenance of such responses have been entertained including molecular mimicry between HIV proteins and self molecules, CD4+ T cell loss accompanied by loss of normal immune regulation that dictate self-non-self-reactivity, defective negative/positive selection of T cells to name a few. The precise mechanisms that lead to such immune dysfunction is difficult to study in humans. Our lab has been studying such autoimmune responses in both SIV-infected RM and sooty mangabeys (SM), a species from Africa that are naturally infected with SIV but do not display any detectable signs of immune deficiency or autoimmunity. We submit that this model is an important model since it allows for narrowing down those mechanisms and pathways that are a result of lentiviral infection per se from those that specifically cause disease including autoimmunity. During the course of these studies, we have ruled out a role for plasma and cellular viral loads, anti-viral humoral responses and a variety of cell signaling pathways. We have identified select pathways that appear to play roles in the pathogenesis of lentiviral infection and disease. These include pathways involved in innocent bystander killing by apoptosis of CD4+ T cells, role for differential regulation of the cell cycle, and a role for distinct host proteins that get incorporated by the virions as they are assembled and either bud out of CD4+ T cells or exit the cells in the form of multi-vesicular endosomal particles from monocytes/macrophages from SIV-infected disease susceptible RM and disease-resistant SM. We present our current working model and hypotheses that are designed to elucidate differences that are responsible for such distinct outcomes of lentiviral infection, autoimmunity and disease. We believe that such findings have important implications for the design of vaccines against human HIV infection.
自身免疫抗体和自身免疫反应在人类HIV感染以及恒河猴（RM）感染SIV的非人灵长类动物模型中均有特征描述，并且被认为与艾滋病的发病机制有关。关于此类反应的诱导和维持，已经提出了许多理论，包括HIV蛋白与自身分子之间的分子模拟、CD4 + T细胞丧失以及正常免疫调节丧失（正常免疫调节决定自身与非自身反应性）、T细胞阴性/阳性选择缺陷等等。导致这种免疫功能障碍的确切机制在人类中很难研究。我们实验室一直在研究SIV感染的恒河猴和乌白眉猴（SM）中的此类自身免疫反应，乌白眉猴是一种来自非洲的物种，自然感染SIV，但未表现出任何可检测到的免疫缺陷或自身免疫迹象。我们认为这个模型很重要，因为它有助于缩小那些由慢病毒感染本身导致的机制和途径，与那些特别导致包括自身免疫在内的疾病的机制和途径。在这些研究过程中，我们排除了血浆和细胞病毒载量、抗病毒体液反应以及多种细胞信号通路的作用。我们已经确定了一些似乎在慢病毒感染和疾病发病机制中起作用的特定途径。这些途径包括CD4 + T细胞凋亡导致的无辜旁观者杀伤途径、细胞周期差异调节的作用，以及不同宿主蛋白的作用，这些宿主蛋白在病毒粒子组装时被整合进去，并从SIV感染的疾病易感恒河猴和抗病乌白眉猴的CD4 + T细胞中出芽或以内体多泡颗粒的形式从单核细胞/巨噬细胞中排出。我们提出了当前的工作模型和假设，旨在阐明导致慢病毒感染、自身免疫和疾病如此不同结果的差异。我们相信这些发现对针对人类HIV感染的疫苗设计具有重要意义。
