SEVERE CD4 T CELL DEPLETION IN SIVSM-INFECTED SOOTY MANGABEYS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类免疫缺陷病毒（HIV）感染与CD 4 + T细胞的进行性耗竭有关，其程度可预测AIDS的发展。最近，研究表明，人类和猕猴的致病性HIV和猿猴免疫缺陷病毒（SIV）感染分别与粘膜组织中记忆CD 4 + T细胞的早期、严重和大部分不可逆的损失相关1-6。因此，已经提出了一种模型，其中粘膜CD 4 + T细胞的这种损失是进展为AIDS的关键决定因素7-10。对自然宿主（如白眉猴）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。与致病性慢病毒感染形成鲜明对比的是，白眉猴的自然SIV感染与艾滋病样疾病无关，尽管多年来感染了高度复制的病毒。白眉猴没有疾病是由于外周CD 4 + T细胞稳态的保存。在这里，我们表明，事实上，无论是慢性的“自然”和急性的“实验”SIV感染的白眉猴的特点是记忆CD 4 + T细胞从肠道和呼吸道粘膜的严重损耗。然而，与致病性HIV/SIV感染相反，白眉猴中MALT CD 4 + T细胞的耗竭发生在低水平免疫激活的背景下，并且可以通过抑制病毒复制来逆转。总之，这些结果表明，MALT相关的CD 4 + T细胞的深度耗竭本身不足以在天然宿主中诱导疾病进展，因此强调了其他免疫学异常（例如，慢性免疫激活和非CD 4+细胞功能障碍）在艾滋病发病机制中的作用。这些数据提供了一个理论基础，探索新的，免疫为基础的方法，除了标准的抗逆转录病毒治疗，在艾滋病毒感染患者的临床管理。

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.