HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-κB

BACKGROUND: Eradication of HIV cannot be achieved with combination antiretroviral therapy (cART) because of the persistence of long-lived latently infected resting memory CD4(+) T cells. We previously reported that HIV latency could be established in resting CD4(+) T cells in the presence of the chemokine CCL19. To define how CCL19 facilitated the establishment of latent HIV infection, the role of chemokine receptor signalling was explored. RESULTS: In resting CD4(+) T cells, CCL19 induced phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt), nuclear factor kappa B (NF-κB), extracellular-signal-regulated kinase (ERK) and p38. Inhibition of the phosphoinositol-3-kinase (PI3K) and Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/ERK signalling pathways inhibited HIV integration, without significant reduction in HIV nuclear entry (measured by Alu-LTR and 2-LTR circle qPCR respectively). Inhibiting activation of MEK1/ERK1/2, c-Jun N-terminal kinase (JNK), activating protein-1 (AP-1) and NF-κB, but not p38, also inhibited HIV integration. We also show that HIV integrases interact with Pin1 in CCL19-treated CD4(+) T cells and inhibition of JNK markedly reduced this interaction, suggesting that CCL19 treatment provided sufficient signals to protect HIV integrase from degradation via the proteasome pathway. Infection of CCL19-treated resting CD4(+) T cells with mutant strains of HIV, lacking NF-κB binding sites in the HIV long terminal repeat (LTR) compared to infection with wild type virus, led to a significant reduction in integration by up to 40-fold (range 1-115.4, p = 0.03). This was in contrast to only a modest reduction of 5-fold (range 1.7-11, p > 0.05) in fully activated CD4(+) T cells infected with the same mutants. Finally, we demonstrated significant differences in integration sites following HIV infection of unactivated, CCL19-treated, and fully activated CD4(+) T cells. CONCLUSIONS: HIV integration in CCL19-treated resting CD4(+) T cells depends on NF-κB signalling and increases the stability of HIV integrase, which allow subsequent integration and establishment of latency. These findings have implications for strategies needed to prevent the establishment, and potentially reverse, latent infection

Tropical forest and peatland conservation in Indonesia: Challenges and directions

Tropical forests and peatlands provide important ecological, climate and socio‐economic benefits from the local to the global scale. However, these ecosystems and their associated benefits are threatened by anthropogenic activities, including agricultural conversion, timber harvesting, peatland drainage and associated fire. Here, we identify key challenges, and provide potential solutions and future directions to meet forest and peatland conservation and restoration goals in Indonesia, with a particular focus on Kalimantan. Through a round‐table, dual‐language workshop discussion and literature evaluation, we recognized 59 political, economic, legal, social, logistical and research challenges, for which five key underlying factors were identified. These challenges relate to the 3Rs adopted by the Indonesian Peatland Restoration Agency (Rewetting, Revegetation and Revitalization), plus a fourth R that we suggest is essential to incorporate into (peatland) conservation planning: Reducing Fires. Our analysis suggests that (a) all challenges have potential for impact on activities under all 4Rs, and many are inter‐dependent and mutually reinforcing, implying that narrowly focused solutions are likely to carry a higher risk of failure; (b) addressing challenges relating to Rewetting and Reducing Fire is critical for achieving goals in all 4Rs, as is considering the local socio‐political situation and acquiring local government and community support; and (c) the suite of challenges faced, and thus conservation interventions required to address these, will be unique to each project, depending on its goals and prevailing local environmental, social and political conditions. With this in mind, we propose an eight‐step adaptive management framework, which could support projects in both Indonesia and other tropical areas to identify and overcome their specific conservation and restoration challenges

FIRST NuSTAR OBSERVATIONS of MRK 501 WITHIN A RADIO to TeV MULTI-INSTRUMENT CAMPAIGN

© 2015. The American Astronomical Society. All rights reserved.. We report on simultaneous broadband observations of the TeV-emitting blazar Markarian 501 between 2013 April 1 and August 10, including the first detailed characterization of the synchrotron peak with Swift and NuSTAR. During the campaign, the nearby BL Lac object was observed in both a quiescent and an elevated state. The broadband campaign includes observations with NuSTAR, MAGIC, VERITAS, the Fermi Large Area Telescope, Swift X-ray Telescope and UV Optical Telescope, various ground-based optical instruments, including the GASP-WEBT program, as well as radio observations by OVRO, Metsähovi, and the F-Gamma consortium. Some of the MAGIC observations were affected by a sand layer from the Saharan desert, and had to be corrected using event-by-event corrections derived with a Light Detection and Ranging (LIDAR) facility. This is the first time that LIDAR information is used to produce a physics result with Cherenkov Telescope data taken during adverse atmospheric conditions, and hence sets a precedent for the current and future ground-based gamma-ray instruments. The NuSTAR instrument provides unprecedented sensitivity in hard X-rays, showing the source to display a spectral energy distribution (SED) between 3 and 79 keV consistent with a log-parabolic spectrum and hard X-ray variability on hour timescales. None (of the four extended NuSTAR observations) show evidence of the onset of inverse-Compton emission at hard X-ray energies. We apply a single-zone equilibrium synchrotron self-Compton (SSC) model to five simultaneous broadband SEDs. We find that the SSC model can reproduce the observed broadband states through a decrease in the magnetic field strength coinciding with an increase in the luminosity and hardness of the relativistic leptons responsible for the high-energy emission

Remarks on two European wigeon x Northern pintail hybrids

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