Role Of Monocytes In AIDS And As Targets For Antiviral Therapy

对艾滋病毒的先天防御（65%） HIV对细胞靶标的感染是由HIV在消除或中和宿主细胞衍生的防御分子方面的能力所辅助和教唆的。 在这些先天性保护分子中，细胞内载脂蛋白B mRNA编辑酶、催化多肽样（APOBEC）胞苷脱氨酶家族组成型表达，但被HIV病毒感染因子（Vif）灭活。I型干扰素是一种在先天性和适应性免疫中具有多种功能的细胞因子，是体外和体内HIV的有效抑制剂，至少部分通过诱导APOBEC 3家族成员发挥其抗病毒活性。 干扰素增强胞苷脱氨酶的能力提供了病毒和靶细胞之间的平衡可能改变有利于宿主的可能性。未经治疗的HIV感染志愿者，无病毒性肝炎，每周接受聚乙二醇化IFN α 2a，持续12周（NIAID合作）。基于这些临床研究，PEG-IFN在HIV单感染患者中具有显著的抗HIV活性，并且这种抗HIV作用与2，5寡腺苷酸合成酶（OAS）蛋白和IFN诱导基因（IFIG）相关。我们通过评估特异性IFIG及其对抑制HIV的贡献，包括APOBEC，BST/tetherin和TRIM 22，研究了降低病毒负荷的机制。 虽然IFN治疗降低了HIV感染者的病毒负荷，但这种细胞因子也会导致免疫功能障碍和毒性，限制了其使用。通过详细绘制IFN受体结合位点，我们合作产生了IFN杂交和突变体（NIAID），并确定影响受体相互作用的螺旋C结构变化改变其限制逆转录病毒复制的能力。我们的数据显示了IFN构建体阻断HIV复制的差异能力，以及HIV抑制的方向幅度与APOBEC 3基因表达水平相关。 作为毒性的标志物，我们证明了某些突变体诱导吲哚胺2，3-双加氧酶（IDO）的表达与亲本IFN相比减少。在与常见的I型IFN受体复合物（IFNAR）以不同的亲和力结合之后，突变体触发离散的或共享的细胞内信号传导途径（Jak/Stat/PI 3 K/NFkB），导致可能与潜在的毒性作用分离的抗病毒调节。通过探索IFN相对于其诱导APOBEC和其他抗病毒分子的能力的结构和功能，可能设计新的IFN相关分子，其保留其在抗病毒和抗肿瘤活性中的有益作用，同时减少在临床施用这种有效的免疫调节剂中出现的毒性。 鸟分枝杆菌对天然因子的调节在大型真菌中的存活（35%） 鸟分枝杆菌复合体（MAC）是一种环境微生物，在免疫功能低下的宿主中引起机会性感染（OI），但很少在健康个体中引起疾病。HIV阳性个体缺乏正常运作的获得性免疫应答，使得M.巨噬细胞内的病毒进展和持久性。此外，免疫重建炎症综合征（IRIS）与短暂的局灶性表现的M。在HIV-1感染者中，开始抗逆转录病毒治疗后持续时间不等的禽流感复合体（MAC）的报告越来越多。重要的是，使用TNF阻断剂治疗自身免疫性疾病也导致各种分枝杆菌属感染/再活化的风险增加。大环内酯是控制M.禽流感病毒感染，但可以成为严重感染的情况下，减少CD 4 + IFN-产生的T细胞发生在艾滋病患者。虽然被认为是IFN缺陷的结果，但仍不清楚M。avium避免先天免疫。感染淋巴结（LN）中巨噬细胞的浸润和滞留反映了主动募集。M.禽流感病毒诱导IL-17的转录，这与尽管T细胞数量减少但在共感染的LN中存在升高的IL-17一致。虽然通常与巨噬细胞无关，但感染巨噬细胞的IL-21基因表达增加可通过维持细胞因子信号传导抑制因子（SOCS）表达而使IFN无反应性永久化。这些数据表明，M.在其巨噬细胞宿主中的禽流感病毒可以部分地使必需的临界质量的巨噬细胞能够窝藏和传播分枝杆菌感染。

Innate defense against HIV (65%) Infection of cellular targets by HIV is aided and abetted by the proficiency of HIV in eliminating or neutralizing host cell-derived defensive molecules. Among these innate protective molecules, a family of intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases is constitutively expressed, but inactivated by HIV viral infectivity factor (Vif). Type I Interferon, a cytokine with a plethora of functions in innate and adaptive immunity and a potent inhibitor of HIV in vitro and in vivo, exerts its anti-viral activity, at least in part by inducing APOBEC3 family members. The ability of IFN to augment cytidine deaminases offered the possibility that the balance between virus and target cell might be altered in favor of the host. Untreated HIV-infected volunteers without viral hepatitis received weekly pegylated IFNalpha2a for 12 weeks (NIAID collaboration). Based on these clinical studies, peg-IFN has significant anti-HIV activity in HIV-mono-infected patients and this anti-HIV effect correlated with 2,5 oligoadenylate synthetase (OAS) protein and IFN inducible genes (IFIG). We examined the mechanisms of reduced viral burden by evaluating specific IFIG and their contribution to inhibition of HIV, including APOBEC, BST/tetherin, and TRIM22. Although IFN therapy reduces viral burden in HIV infected individuals, this cytokine can also cause immune dysfunction and toxicities, limiting its use. Through detailed mapping of IFN receptor binding sites, we collaboratively generated IFN hybrids and mutants(NIAID)and determined that structural changes in helix C that influence receptor interactions alter its ability to limit retroviral replication. Our data show a differential ability of IFN constructs to block HIV replication, and the directional magnitude of HIV inhibition correlated with levels of APOBEC3 gene expression. As a marker of toxicity, we demonstrated that certain mutants induced reduced expression of indoleamine 2,3-dioxygenase (IDO) compared to parental IFN. Subsequent to binding with distinct affinities to the common type I IFN receptor complex (IFNAR), the mutants trigger discreet or shared intracellular signaling pathways (Jak/Stat/PI3K/NFkB) leading to antiviral regulation that may be dissociated from underlying toxic effects. By exploring structure and function of IFN relative to its ability to induce APOBEC and other anti-viral molecules, it may become possible to design novel IFN-related molecules, which preserve its beneficial roles in anti-viral and anti-tumor activity while reducing toxicities that arise in the clinical administration of this potent immunomodulator. Regulation of Innate Factors by Mycobacterium avium Perpetuates Survival in Macrophages(35%) Mycobacterium avium complex (MAC) is an environmental microorganism that causes opportunistic infections (OI) in immunocompromised hosts, but rarely causes illness in healthy individuals. Absence of a properly functioning acquired immune response in HIV+ individuals allows M. avium progression and persistence within macrophages. Also, immune reconstitution inflammatory syndrome (IRIS) with a transient focal manifestation of M. avium complex (MAC) of variable duration after the initiation of antiretroviral therapy has been increasingly reported in HIV-1 infected individuals. Importantly, the use of TNF blockers for the treatment of autoimmune diseases has also led to an increased risk of infection/reactivation with various mycobacteria species. Macrophages are essential in controlling M. avium infection, but can become heavily infected in a situation of reduced CD4+ IFN-producing T cells as occurs in AIDS patients. While considered a consequence of deficiencies in IFN, it is still unclear how M. avium averts innate immunity. Infiltration and retention of macrophages in infected lymph nodes (LN) reflect active recruitment. In vitro infection of macrophages with M. avium induces the transcription of IL-17, consistent with the presence of elevated IL-17 in co-infected LN despite the reduced number of T cells. Although not normally associated with macrophages, increased IL-21 gene expression by infected macrophages can perpetuate IFN unresponsiveness by sustaining suppressors of cytokine signaling (SOCS) expression. These data suggest that induction of IL-17 and IL-21 by M. avium in its macrophage hosts may, in part, enable the requisite critical mass of macrophages to harbor and propagate mycobacterial infections.