SAMHD1-Deficient CD14+ Cells from Individuals with Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor

The first multi-model ensemble of regional climate simulations at kilometer-scale resolution, part I: evaluation of precipitation

Here we present the first multi-model ensemble of regional climate simulations at kilometer-scale horizontal grid spacing over a decade long period. A total of 23 simulations run with a horizontal grid spacing of ∼3 km, driven by ERA-Interim reanalysis, and performed by 22 European research groups are analysed. Six different regional climate models (RCMs) are represented in the ensemble. The simulations are compared against available high-resolution precipitation observations and coarse resolution (∼ 12 km) RCMs with parameterized convection. The model simulations and observations are compared with respect to mean precipitation, precipitation intensity and frequency, and heavy precipitation on daily and hourly timescales in different seasons. The results show that kilometer-scale models produce a more realistic representation of precipitation than the coarse resolution RCMs. The most significant improvements are found for heavy precipitation and precipitation frequency on both daily and hourly time scales in the summer season. In general, kilometer-scale models tend to produce more intense precipitation and reduced wet-hour frequency compared to coarse resolution models. On average, the multi-model mean shows a reduction of bias from ∼ −40% at 12 km to ∼ −3% at 3 km for heavy hourly precipitation in summer. Furthermore, the uncertainty ranges i.e. the variability between the models for wet hour frequency is reduced by half with the use of kilometer-scale models. Although differences between the model simulations at the kilometer-scale and observations still exist, it is evident that these simulations are superior to the coarse-resolution RCM simulations in the representing precipitation in the present-day climate, and thus offer a promising way forward for investigations of climate and climate change at local to regional scales

Restriction of HIV-1 Replication in Monocytes Is Abolished by Vpx of SIVsmmPBj

Background: Human primary monocytes are refractory to infection with the human immunodeficiency virus 1 (HIV-1) or transduction with HIV-1-derived vectors. In contrast, efficient single round transduction of monocytes is mediated by vectors derived from simian immunodeficiency virus of sooty mangabeys (SIVsmmPBj), depending on the presence of the viral accessory protein Vpx. Methods and Findings: Here we analyzed whether Vpx of SIVsmmPBj is sufficient for transduction of primary monocytes by HIV-1-derived vectors. To enable incorporation of PBj Vpx into HIV-1 vector particles, a HA-Vpr/Vpx fusion protein was generated. Supplementation of HIV-1 vector particles with this fusion protein was not sufficient to facilitate transduction of human monocytes. However, monocyte transduction with HIV-1-derived vectors was significantly enhanced after delivery of Vpx proteins by virus-like particles (VLPs) derived from SIVsmmPBj. Moreover, pre-incubation with Vpx-containing VLPs restored replication capacity of infectious HIV-1 in human monocytes. In monocytes of non-human primates, single-round transduction with HIV-1 vectors was enabled. Conclusion: Vpx enhances transduction of primary human and even non-human monocytes with HIV-1-derived vectors, only if delivered in the background of SIVsmmPBj-derived virus-like particles. Thus, for accurate Vpx function the presence of SIVsmmPBj capsid proteins might be required. Vpx is essential to overcome a block of early infection steps in primary monocytes

The first multi-model ensemble of regional climate simulations at kilometer-scale resolution. Part I: Evaluation of precipitation

Here we present the first multi-model ensemble of regional climate simulations at kilometer-scale horizontal grid spacing over a decade long period. A total of 23 simulations run with a horizontal grid spacing of ∼ 3 km, driven by ERA-Interim reanalysis, and performed by 22 European research groups are analysed. Six different regional climate models (RCMs) are represented in the ensemble. The simulations are compared against available high-resolution precipitation observations and coarse resolution (∼ 12 km) RCMs with parameterized convection. The model simulations and observations are compared with respect to mean precipitation, precipitation intensity and frequency, and heavy precipitation on daily and hourly timescales in different seasons. The results show that kilometer-scale models produce a more realistic representation of precipitation than the coarse resolution RCMs. The most significant improvements are found for heavy precipitation and precipitation frequency on both daily and hourly time scales in the summer season. In general, kilometer-scale models tend to produce more intense precipitation and reduced wet-hour frequency compared to coarse resolution models. On average, the multi-model mean shows a reduction of bias from ∼ −40 at 12 km to ∼ −3 at 3 km for heavy hourly precipitation in summer. Furthermore, the uncertainty ranges i.e. the variability between the models for wet hour frequency is reduced by half with the use of kilometer-scale models. Although differences between the model simulations at the kilometer-scale and observations still exist, it is evident that these simulations are superior to the coarse-resolution RCM simulations in the representing precipitation in the present-day climate, and thus offer a promising way forward for investigations of climate and climate change at local to regional scales. © 2021, The Author(s)

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None