120 research outputs found
Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection
The direct link between sustained type I interferon (IFN-I) signaling and HIV-1-induced immunopathogenesis during chronic infection remains unclear. Here we report studies using a monoclonal antibody to block IFN-α/β receptor 1 (IFNAR1) signaling during persistent HIV-1 infection in humanized mice (hu-mice). We discovered that, during chronic HIV-1 infection, IFNAR blockade increased viral replication, which was correlated with elevated T cell activation. Thus, IFN-Is suppress HIV-1 replication during the chronic phase but are not essential for HIV-1-induced aberrant immune activation. Surprisingly, IFNAR blockade rescued both total human T cell and HIV-specific T cell numbers despite elevated HIV-1 replication and immune activation. We showed that IFNAR blockade reduced HIV-1-induced apoptosis of CD4+ T cells. Importantly, IFNAR blockade also rescued the function of human T cells, including HIV-1-specific CD8+ and CD4+ T cells. We conclude that during persistent HIV-1 infection, IFN-Is suppress HIV-1 replication, but contribute to depletion and dysfunction of T cells
Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice
The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment
Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs
Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1–infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1–induced immune hyperactivation and rescued anti–HIV-1 immune responses in T cells from HIV-1–infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1–associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART
Characterization of species-specific genes regulated by E2-2 in human plasmacytoid dendritic cells
Dendritic cells (DCs) are sentinels of the immune system and comprise two distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Human pDCs are distinguished from mouse pDCs phenotypically and functionally. Basic helix-loop-helix protein E2-2 is defined as an essential transcription factor for mouse pDC development, cell fate maintenance and gene programe. It is unknown whether E2-2 regulation contributes to this species-specific difference. Here we investigated the function of E2-2 in human pDCs and screened human-specific genes regulated by E2-2. Reduced E2-2 expression in human pDC cell line GEN2.2 resulted in diminished IFN-α production in response to CpG but elevated antigen presentation capacity. Gene expression profiling showed that E2-2 silence down-regulated pDC signature genes but up-regulated cDC signature genes. Thirty human-specific genes regulated by E2-2 knockdown were identified. Among these genes, we confirmed that expression of Siglec-6 was inhibited by E2-2. Further more, Siglec-6 was expressed at a higher level on a human pDC subset with drastically lower expression of E2-2. Collectively, these results highlight that E2-2 modulates pDC function in a species-specific manner, which may provide insights for pDC development and functions
Quasi-solid-state electrolyte for rechargeable high-temperature molten salt iron-air battery
Molten salts are a unique type of electrolyte enabling high-temperature electrochemical energy storage (EES) with unmatched reversible electrode kinetics and high ion-conductivities, and hence impressive storage capacity and power capability. However, their high tendency to evaporate and flow at high temperatures challenges the design and fabrication of the respective EES devices in terms of manufacturing cost and cycling durability. On the other hand, most of these EES devices require lithium-containing molten salts as the electrolyte to enhance performances, which not only increases the cost but also demands a share of the already limited lithium resources. Here we report a novel quasi-solid-state (QSS) electrolyte, consisting of the molten eutectic mixture of Na2CO3-K2CO3 and nanoparticles of yttrium stabilized zirconia (YSZ) in a mass ratio of 1:1. The QSS electrolyte has relatively lower volatility in comparison with the pristine molten Na2CO3-K2CO3 eutectic, and therefore significantly suppresses the evaporation of molten salts, thanks to a strong interaction at the interface between molten salt and YSZ nanoparticles at high temperatures. The QSS electrolyte was used to construct an iron-air battery that performed excellently in charge-discharge cycling with high columbic and energy efficiencies. We also propose and confirm a redox mechanism at the three-phase interlines in the negative electrode. These findings can help establish a simpler and more efficient approach to designing low-cost and high-performance molten salt metal-air batteries with high stability and safety
Solar Ring Mission: Building a Panorama of the Sun and Inner-heliosphere
Solar Ring (SOR) is a proposed space science mission to monitor and study the
Sun and inner heliosphere from a full 360{\deg} perspective in the ecliptic
plane. It will deploy three 120{\deg}-separated spacecraft on the 1-AU orbit.
The first spacecraft, S1, locates 30{\deg} upstream of the Earth, the second,
S2, 90{\deg} downstream, and the third, S3, completes the configuration. This
design with necessary science instruments, e.g., the Doppler-velocity and
vector magnetic field imager, wide-angle coronagraph, and in-situ instruments,
will allow us to establish many unprecedented capabilities: (1) provide
simultaneous Doppler-velocity observations of the whole solar surface to
understand the deep interior, (2) provide vector magnetograms of the whole
photosphere - the inner boundary of the solar atmosphere and heliosphere, (3)
provide the information of the whole lifetime evolution of solar featured
structures, and (4) provide the whole view of solar transients and space
weather in the inner heliosphere. With these capabilities, Solar Ring mission
aims to address outstanding questions about the origin of solar cycle, the
origin of solar eruptions and the origin of extreme space weather events. The
successful accomplishment of the mission will construct a panorama of the Sun
and inner-heliosphere, and therefore advance our understanding of the star and
the space environment that holds our life.Comment: 41 pages, 6 figures, 1 table, to be published in Advances in Space
Researc
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