Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2019 Jul 3;10:1537. doi: 10.3389/fimmu.2019.01537. eCollection 2019.
HIV infected individuals have been shown to be pre-disposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in lung innate immunity, but contradictory results have been reported regarding their functionality following HIV infection. Here, using the SIV rhesus macaque model, we document the effect of SIV infection on the phenotypic and functional properties of AMs. Following infection with SIV, AMs in bronchoalveolar lavage (BAL) sampled over 2- to 20-weeks post-infection (wpi) were compared to those in BAL samples from naïve macaques. AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques ( < 0.0001 for all), but dropped significantly with progression to chronic infection. Phagocytic activity of AMs 2-and 4-wpi was elevated compared to AMs of naive animals ( = 0.0005, = 0.0004, respectively) but significantly decreased by 12-wpi ( = 0.0022, = 0.0019, respectively). By 20-wpi the ability of AMs from chronically infected animals to perform SIV-specific antibody-dependent phagocytosis (ADP) was also diminished ( = 0.028). Acute SIV infection was associated with increased FcγRIII expression which subsequently declined with disease progression. Frequency of FcγRIII AMs showed a strong trend toward correlation with SIV-specific ADP, and at 2-wpi FcγRIII expression negatively correlated with viral load ( = -0.6819; = 0.0013), suggesting a contribution to viremia control. Importantly, PD-1 was found to be expressed on AMs and showed a strong trend toward correlation with plasma viral load ( = 0.8266; = 0.058), indicating that similar to over-expression on T-cells, PD-1 expression on AMs may also be associated with disease progression. Further, AMs predominantly expressed PD-L2, which remained consistent over the course of infection. PD-1 blockade enhanced SIV-specific ADP by AMs from chronic infection indicating that the PD-1/PD-L2 pathway may modulate functional activity of AMs at that stage. These findings provide new insight into the dynamics of SIV infection leading to AM dysfunction and alteration of pulmonary innate immunity. Our results suggest new pathways to exploit in developing therapies targeting pulmonary disease susceptibility in HIV-infected individuals.
HIV 感染者即使接受抗逆转录病毒治疗，也易发生肺部感染。肺泡巨噬细胞（AM）在肺固有免疫中发挥关键作用，但 HIV 感染后其功能的研究结果存在争议。在这里，我们使用 SIV 恒河猴模型，记录了 SIV 感染对 AM 表型和功能特性的影响。在感染 SIV 后，与未感染的猕猴 BAL 样本相比，在感染后 2-20 周（wpi）采集的 BAL 中 AM 表达的促炎细胞因子 TNF-α、IL-6、IL-1β 和趋化因子 RANTES 在 2 wpi 时急剧增加（均 < 0.0001），但随着慢性感染的进展，这些细胞因子显著减少。2 和 4 wpi 时 AM 的吞噬活性与未感染动物相比升高（分别为 = 0.0005，= 0.0004），但在 12 wpi 时显著降低（分别为 = 0.0022，= 0.0019）。在 20 wpi 时，慢性感染动物 AM 进行 SIV 特异性抗体依赖性吞噬作用（ADP）的能力也降低（= 0.028）。急性 SIV 感染与 FcγRIII 表达增加有关，随后随着疾病的进展而下降。FcγRIII AM 的频率与 SIV 特异性 ADP 呈强烈的趋势相关，在 2 wpi 时，FcγRIII 表达与病毒载量呈负相关（= -0.6819；= 0.0013），提示其可能有助于控制病毒血症。重要的是，PD-1 在 AM 上表达，并与血浆病毒载量呈强烈的趋势相关（= 0.8266；= 0.058），表明与 T 细胞上的过度表达一样，PD-1 在 AM 上的表达也可能与疾病进展有关。此外，AM 主要表达 PD-L2，在整个感染过程中保持一致。PD-1 阻断增强了慢性感染 AM 的 SIV 特异性 ADP，表明 PD-1/PD-L2 途径可能在该阶段调节 AM 的功能活性。这些发现为 SIV 感染导致 AM 功能障碍和改变肺固有免疫的动态提供了新的见解。我们的结果表明，针对 HIV 感染个体的肺部疾病易感性，存在新的治疗靶点途径。
