Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells.

HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+ T cells. Furthermore, Naf1 knockdown in resting CD4+ T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy. IMPORTANCE: HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.

Mast Cell Activation Triggered by Retrovirus Promotes Acute Viral Infection.

Mast cells (MCs) are strategically located at the host-environment interface and their non-allergic roles in the immune-surveillance of pathogens have recently gained more attention. However, MC-caused detrimental regulation of immune inflammations can promote viral invasion. Currently, the role of MCs in retroviral infection remains elusive. We have recently proved that human gut MCs could capture and transfer HIV-1 to CD4+ T cells for promoting viral spread; MC-released histamine augments HIV-1-induced functional polarization of dendritic cells to cause immunosuppression via stimulating the differentiation of regulatory T cells. In this study, we used a murine model of MuLV/Friend virus infection to address MC role in acute retroviral infection in vivo. The acute infection of MuLV/Friend virus could be established in C57BL/6 wild type mice, but viral acquisition showed low efficiency in C57BL/6-Kit W - sh/W - sh (Sash) mice which lack MCs. In mechanism, we found that MuLV/Friend virus triggered MC activation for degranulation; MC degranulation subsequently activated the granulocyte-like myeloid derived suppressive cells (G-MDSCs) to inhibit CD8+ T cells- and NK cells-mediated antiviral immune responses. The reconstruction of MCs in Sash mice promoted acute retroviral infection by regulating G-MDSCs functions and antiviral immune responses. Importantly, the administration of MC stabilizers to block cell degranulation elevated antiviral immune response and consequently suppressed retrovirus infection. This study uncovers a specific role of MCs in acute retroviral infection and elucidates the underlying immune-mechanisms. Targeting MCs may provide a novel approach for controlling acute infection by retroviruses.

[Effect of acupuncture and moxibustion on brain functional connectivity network in patients with refractory facial paralysis].

OBJECTIVE: To observe the effects of acupuncture on resting-state functional connectivity (rs-FC) in patients with refractory peripheral facial paralysis, and to preliminarily explore the central mechanism of acupuncture for this disease. METHODS: Twenty patients with refractory peripheral facial paralysis were selected as subject and treated with acupuncture at Qianzheng (EX-HN 16), Fengchi (GB 20), Cuanzhu (BL 2), Dicang (ST 4), Jiache (ST 6), Shuigou (GV 26), Chengjiang (CV 24), Yifeng (TE 17), Touwei (ST 8), Sibai (ST 2), Yingxiang (LI 20) and Hegu (LI 4), once every other day, three times a week, 15 times as a course of treatment. The 1-course treatment was given. The score of Sunnybrook (Toronto) facial grading system was used to evaluate the clinical efficacy before and after the treatment. In addition, 20 healthy volunteers were selected as control. For patients, the resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment, for healthy volunteers, the scans were performed when they were recruited. The brain magnetic resonance images were analyzed with left primary motor area (LMⅠ) and right primary motor area (RMⅠ) as regions of interest. The differences of rs-FC between patients with refractory peripheral facial paralysis before and after treatment and healthy volunteers were compared. RESULTS: Compared before treatment, the Sunnybrook score was increased after the treatment (P<0.05). Compared with healthy volunteers, the functional connection between bilateral primary motor areas (MⅠ) and multiple brain areas were enhanced in patients before treatment, and most of brain areas were located in the anterior motor area (middle frontal gyrus, superior frontal gyrus), posterior central gyrus, anterior cuneiform lobe, middle temporal gyrus, inferior temporal gyrus and cerebellum lobe. Compared before treatment, the left inferior frontal gyrus was the strong functional connection area between LMⅠ and whole brain after acupuncture treatment, and there was no significant difference between RMⅠ and resting-state whole brain. Compared with healthy volunteers, the functional connections between bilateral MⅠ and multiple brain regions were enhanced after acupuncture, and most of the main brain regions were consistent with those before treatment. CONCLUSION: (1) Acupuncture could effectively improve the clinical symptoms of refractory peripheral facial paralysis. (2) The brain function of patients with refractory peripheral facial paralysis has been changed before acupuncture, which may be caused by the reactive compensation of the brain. (3) Acupuncture could enhance the functional connection between LMⅠ and left inferior frontal gyrus to promote the compensatory response, which may be one of the central mechanisms of acupuncture for refractory peripheral facial paralysis.