Myeloid - T cell interactions that sustain SIV reservoirs during effective antire

在最佳治疗的患者中，HIV持续存在是通过维持转录沉默来维持的。 细胞群中的前病毒基因组是长寿的或周转缓慢的，和/或通过持续的低水平的 病毒复制导致靶细胞的从头感染。本次合作的一个中心主题是， HIV的这种持久性/潜伏期是通过CD 4 [+] T细胞之间基于组织的相互作用来维持的， 通过一种或多种机制，包括：（1）HIV的有效细胞间转移;（2） 导致CD 4 [+] T细胞功能障碍和抗病毒反应受损的调节信号;（3）髓系 向CD 4 [+] T细胞发出信号，导致转录沉默的维持;和（4）炎症信号 这导致CD 4 [+] T细胞活化，并增加新发感染或潜伏性T细胞再活化的风险。 感染细胞和补充长寿的感染细胞。此外，艾滋病毒感染可能诱发因素 促进受感染细胞的存活，从而促进长寿病毒库的存活。为了确定这些 机制是可操作的，我们将首先系统地询问最佳治疗的组织空间。 宿主，以便可以确定潜在的和活跃复制的储库的位置和大小。给定 影响这些机制的治疗药物的可用性，然后我们将明确测试， 它们单独或共同对病毒持久性/潜伏期的贡献程度。在这个项目中， 方法是在恒河猴（Macaca mulatta）感染SIV的背景下， 实验的具体目的如下：（1）确定是否以及如何持续复制的病灶 和/或潜伏病毒通过病理性骨髓-T细胞相互作用在最佳治疗的宿主中持续存在;（2） 确定是否可以通过抑制吲哚胺2，3- 双加氧酶（IDO），一种介导骨髓炎性细胞因子促炎作用的免疫调节酶， CD 4 + T细胞上的细胞;和（3）确定是否可以通过以下方式减少持久性/潜伏性病毒库： 抑制单核细胞集落刺激因子（MCSF），一种由SIV/HIV上调的细胞因子， 防止巨噬细胞凋亡。

HIV persistence in the optimally-treated patient is sustained by the maintenance of transcriptionally-silent proviral genomes within cell populations that are long-lived or that turn over slowly, and/or by ongoing low-level viral replication leading to de novo infection of target cells. It is a central theme of this Collaboratory that such persistence/latency of HIV is maintained by tissue-based interactions between CD4[+] T cells and myeloid cells through one or more mechanisms, including: (1) efficient cell-to-cell transfer of HIV; (2) regulatory signals that result in CD4[+] T cell dysfunction and impairment of the antiviral response; (3) myeloid signaling to CD4[+] T cells that results in maintenance of transcriptional silencing; and (4) inflammatory signals which result in CD4[+] T cell activation and increased risk of either de novo infection or reactivation of latently infected cells and replenishment of long-lived infected cells. Additionally, HIV infection may induce factors that promote survival of infected cells and, hence, of a long-lived viral reservoir. To determine which of these mechanisms are operative, we will first systemically interrogate the tissue spaces of the optimally treated host, so that the location and size of the latent and actively replicating reservoir can be determined. Given the availability of therapeutic agents that impact upon these mechanisms, we will then test definitively to what extent they might contribute to virus persistence/latency, alone or in concert. In this Project, this approach is taken in the context of SIV infection of the rhesus macaque (Macaca mulatta), pursuing experiments in the following Specific Aims: (1) to determine whether and how foci of persistently replicating and/or latent virus are sustained in the optimally-treated host by pathologic myeloid-T cell interactions; (2) to determine whether the persistent/latent virus pool can be diminished by inhibition of indoleamine 2,3- dioxygenase (IDO), an immunoregulatory enzyme that mediates the pro-inflammatory effects of myeloid cells on CD4+ T cells; and (3) to determine whether the persistent/latent virus pool can be diminished by inhibition of monocyte colony stimulating factor (MCSF), a cytokine which is upregulated by SIV/HIV and that prevents apoptosis of macrophages.