The Role of Gamma Delta T Cells as Persistent Reservoirs of HIV Infection

 描述(由申请人提供)：根除艾滋病毒感染将需要识别所有潜伏感染的细胞宿主。我们已经发现了dT 细胞构成了一个意想不到的但实质性的持续、潜伏感染的储备库。我们从长期接受抗逆转录病毒治疗的18名无菌血症患者中的14名Vd2类高度纯化的T细胞中恢复了潜伏但具有复制能力的HIV。在这14名患者中，有9名在培养了15,000个细胞后艾滋病毒得以恢复，这反映出感染的频率很高。我们发现原代分离的外周血Vd2细胞可以通过激活诱导的CD4受体上调而在体外被感染，并提示HIV诱导的免疫激活可能允许在体内感染d T细胞。我们建议扩展我们对Vd2 T细胞潜伏感染的研究，调查Vd1 T细胞以确定它们是否也被潜伏感染，然后进行纵向研究以验证这种新的储存库中感染的持久性并更准确地量化感染。然后我们将探索这些细胞中的潜伏期是否可以 被我们小组正在开发的针对中央记忆CD4+T细胞潜伏期的相同治疗方法所扰乱，或者如果需要针对这个储存库的新的、d-特异性的方法。最后，鉴于d T细胞在组织中的优势，我们将直接研究这些细胞在高尔特和淋巴组织中的感染和潜伏期。我们的研究将对定义和打击持续、潜伏感染细胞中的艾滋病毒感染做出关键贡献。

 DESCRIPTION (provided by applicant): Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. We have discovered that d T cells constitute an unexpected but substantial reservoir of persistent, latent infection. We recovered latent but replication-competent HIV from highly purified T cells of the Vd2 class from 14 of 18 aviremic patients on long-standing antiretroviral therapy. In nine of these 14 patients, HIV was recovered when as few as 15,000 cells were cultured, reflecting a high frequency of infection. We found that primary isolated peripheral blood Vd2 cells can be infected in vitro through activation-induced upregulation of the CD4 receptor and propose that HIV-induced immune activation may allow infection of d T cells in vivo. We propose to extend our studies of latent infection in Vd2 T cells, survey Vd1 T cells to determine if they are latently infected as well, and then perform longitudinal studies to verify the persistence and more accurately quantitate infection in this new reservoir. We will then explore whether latency in these cells can be disrupted by the same therapeutic approaches that our group is developing to target latency within central memory CD4+ T cells, or if novel, d-specific approaches to this reservoir are needed. Finally, given the predominance of d T cells within the tissue we will directly study infection and latency of these cells in GALT and lymph node tissue. Our investigations will contribute critically to the effort to define and attack HIV infection within persistent, latently infected cells.