SEVERE CD4 T CELL DEPLETION IN SIVSM-INFECTED SOOTY MANGABEYS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类免疫缺陷病毒(HIV)感染与CD4+T细胞的进行性耗尽有关，其程度预示着艾滋病的发展。最近的研究表明，人类感染HIV和猴免疫缺陷病毒(SIV)分别与粘膜组织1-6早期、严重且在很大程度上不可逆转地丧失记忆的CD4+T细胞有关。因此，已经提出了一种模型，根据该模型，粘膜CD4+T细胞的这种丧失是进展为艾滋病7-10的关键决定因素。对自然宿主的非致病性SIV感染的研究为HIV感染的发病机制提供了重要的见解。与致病的慢病毒感染形成鲜明对比的是，尽管多年来感染了一种高度复制的病毒，但芒果鱼的自然SIV感染与艾滋病样疾病无关。爪哇鱼的无病可归因于外周CD4+T细胞内稳态的保存。在这里，我们表明，事实上，无论是慢性的自然感染还是急性的实验性SIV感染，芒果鸟的特征都是肠道和呼吸道粘膜中记忆的CD4+T细胞严重耗尽。然而，与致病的HIV/SIV感染相反，MALT CD4+T细胞的耗尽发生在免疫激活水平较低的情况下，可以通过抑制病毒复制来逆转。总之，这些结果表明，与MALT相关的CD4+T细胞的严重枯竭本身并不足以在自然宿主中诱导疾病进展，因此强调了其他免疫异常(例如，慢性免疫激活和非CD4+细胞功能障碍)在艾滋病发病中的作用。这些数据为探索新的、基于免疫的方法提供了理论基础，除了标准的抗逆转录病毒治疗外，还可以在艾滋病毒感染患者的临床管理中使用这些方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human Immunodeficiency Virus (HIV) infection is associated with a progressive depletion of CD4+ T-cells whose extent predicts development of AIDS. Recently, it was shown that pathogenic HIV and simian immunodeficiency virus (SIV) infections of humans and macaques, respectively, are associated with an early, severe and largely irreversible loss of memory CD4+ T-cells in mucosal tissues 1-6. As such, a model has been proposed whereby this loss of mucosal CD4+ T-cells is a key determinant of progression to AIDS 7-10. Important insights into the pathogenesis of HIV infection have been provided by studies of non-pathogenic SIV infection of natural hosts, such as the sooty mangabeys. In marked contrast to pathogenic lentiviral infections, natural SIV infection of mangabeys is not associated with an AIDS-like disease despite many years of infection with a highly replicating virus. The absence of disease in mangabeys has been attributed to the preservation of peripheral CD4+ T-cell homeostasis. Here we show that, in fact, both chronic "natural" and acute "experimental" SIV infections of mangabeys are characterized by a severe depletion of memory CD4+ T-cells from the intestinal and respiratory mucosa. However, in contrast to pathogenic HIV/SIV infections, the depletion of MALT CD4+ T-cells in mangabeys occurs in the context of low levels of immune activation and can be reverted by suppressing virus replication. In all, these results indicate that a profound depletion of MALT-associated CD4+ T cells is not sufficient per se to induce disease progression in a natural host, thus emphasizing the role of other immunological abnormalities (e.g., chronic immune activation and dysfunction of non-CD4+ cells) in the pathogenesis of AIDS. These data provide a rationale for exploring new, immune-based approaches, in addition to standard antiretroviral therapy, in the clinical management of HIV-infected patients.