Suchergebnisse

El objetivo de la presente investigación fue determinar cuáles son las bases filosóficas y jurídicas para la adecuada tipificación y aplicación de la legítima defensa en diversas conductas sociales en la legislación Peruana. El tipo de investigación fue el descriptivo correlacional, y el diseño fue el no experimental. La población estuvo conformada por 73 personas: jueces, abogados colegiados y hábiles y catedráticos universitarios de la ciudad de Iquitos. La muestra estuvo conformada por el 100% de la población. La técnica fue la encuesta y el análisis documental, y los instrumentos utilizados fueron tres cuestionarios: dirigido a jueces, abogados colegiados hábiles y a catedráticos universitarios. Para el análisis estadístico se utilizaron cifras absolutas y relativas. Conclusiones: La legítima defensa, que es la causa de justificación por excelencia, tiene como principios básicos en primer lugar, el de la autodeterminación y, en segundo lugar, el de la prevalencia del derecho ya que toda persona tiene el derecho constitucional de defenderse ante un ataque injusto (defensa propia) y también la defensa de otras personas (defensa de terceros), es un derecho fundamental y natural de toda persona; La agresión ilegítima, la necesidad racional del medio empleado y la falta de provocación suficiente de quien hace la defensa tienen que ser concurrentes según la normativa penal peruana, pero también deben tenerse en cuenta los aspectos subjetivos de la misma (reconocimiento de la situación de justificación). Este aspecto subjetivo no ha sido mencionado en la Ley materia de análisis. La redacción del Art. 20° inc. 3 del Código Penal Peruano, que tipifica la Legítima Defensa, está incompleta, puesto que no considera en forma específica algunos hechos que aclaran este derecho, aplicando los Principios Filosóficos de esta doctrina, como por ejemplo que "Se presume que actúa en legítima defensa quien razonablemente repele al que, sin su consentimiento, ha ingresado a su residencia, morada, casa o habitación", como sucede en el derecho comparado, específicamente en el derecho penal panameño. En el Perú los que hacen uso de este derecho a la legítima defensa, en la mayoría de casos son procesados, investigados, y pasan por la ordalía de un proceso Penal. Existen innumerables casos en los que la aplicación de la legítima defensa fue materia de una errónea o inapropiada interpretación por jueces y fiscales. ; The objective of show it(subj) investigation was to determine to which ones the philosophical and juridical bases are for the made suitable characterization and application of the self-defense in diverse social conducts in the Peruvian legislation. The fact-finding fellow was the descriptive correlacional, and the design was experimental no. The population was shaped for 73 people: Judges, collegiate and able lawyers and university professors urban of Iquitos. The sign was shaped for the 100. technique was the opinion poll and the documentary analysis, and the instruments utilizados were three questionnaires: Guided to judges, collegiate lawyers able and to university professors. They utilized absolute and relative numbers in order to the statistical analysis. Conclusions: The self-defense, that he is the cause of justification par excellence, has as basic beginnings in the first place, the of the self-determination and, in the second place, the of the right's prevalence since every person has to defend oneself in front of an attack unjust constitutional right (self-defense) and also someone elses's the defense ( third-party defense ), he is a fundamental right and every person's native; The illegitimate aggression, the rational need of the half employee and the provocation lack that he makes the defense enough of have to be concurring according to the penal ground rules Peruvian, but also they must have in bill subjective aspects thereof ( recognition of the justification situation). This subjective aspect has not been mentioned in the law analysis matter. The Art's wording. 20.The one that do this right's use to the self-defense, in the majority of cases stand trial In the Perú, investigados, and they are taken as a Penal process's trial by ordeal. Innumerable cases that the self-defense's application was matter of an erroneous or improper interpretation for judges and district attorneys in exist. ; Tesis

IntroductionPrevious studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1–3] It is unknown, however, if TDF has an intrinsic lipid‐lowering effect or such findings are due to the addition or removal of other offending agents or other reasons.Materials and MethodsThis was a randomized, crossover, double‐blind, placebo‐controlled clinical trial (NCT 01458977). Subjects with HIV‐1 RNA <50 copies/mL during at least 6 months on stable DRV/r (800/100 mg QD) or LPV/r (400/100 mg BID) monotherapy, with confirmed fasting total cholesterol ≥200 or LDL‐cholesterol ≥130 mg/dL and not taking lipid‐lowering drugs were randomized to (A) adding TDF/FTCduring 12 weeks followed by 24 weeks without TDF/FTC, or (B) continuing without TDF/FTC for 12 weeks, adding TDF/FTC for 12 weeks and then withdrawing TDF/FTC for 12 additional weeks. Randomization was stratified by DRV/r or LPV/r use at study entry. All subjects received a specific dietary counselling. Primary endpoints were changes in median fasting total, LDL and HDL‐cholesterol 12 weeks after TDF/FTC addition. Analyses were performed by ITT.Results46 subjects with a median age of 43 (40–48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL‐cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL‐cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL‐cholesterol (p<0.001) and HDL‐cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total‐cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL‐cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure.ConclusionCoformulated TDF/FTC has an intrinsic lipid‐lowering effect, likely attributable to TDF.

IntroductionSeveral resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance mutations on CD4 slopes in patients undergoing episodes of viral failure.Materials and MethodsPatients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test during the episode were included. Mutations were identified using the IAS‐US (2013) list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log‐scale), risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope.ResultsA total of 2731 patients experiencing a median of 1 (range 1–4) episodes were included in this analysis. The prevalence of any resistance per episode was 88.4%; NNRTI resistance was most common (78.5%). Overall, CD4 counts declined by 17.1 (−19.7; −14.5) cells per year; this decline was less marked with partial viral suppression (current HIV RNA more than 1.5 log below the setpoint; p=0.01). In multivariable models adjusting for viral load, CD4 decline was slower during episodes with detected resistance compared to episodes without detected resistance (21.0 cells/year less, 95% CI 11.75–30.31, p<0.001). Among those with more than one resistance mutation, there was only weak evidence that class‐specific mutations had any effect on the CD4 slope (Table 1). The effects of individual mutations (incl. M184V) were explored, but none were significantly associated with the CD4 slope; for these comparisons, a Bonferroni‐corrected p‐value level was 0.003.ConclusionsIn our study population, detected resistance was associated with slightly less steep CD4 declines. This may be due to a biological effect of resistance on CD4 slopes, or other unmeasured factors such as poor adherence among individuals without resistance. Among individuals with detected drug resistance, we found no evidence suggesting that the presence of individual mutations was associated with beneficial CD4 slope changes.

IntroductionIt is uncertain if plasma HIV‐1 tropism is an independent predictor of short‐term risk of clinical progression / death, in addition to the CD4 count and HIV RNA level. We conducted a nested case‐control study within EuroSIDA to assess this question amongst people with current HIV RNA level >1000 copies/mL, including both people on ART and those ART naïve.MethodsPeople with an AIDS diagnosis or who died from any causes for whom there was a stored plasma sample with HIV‐1 RNA (VL)≥1,000 copies/mL available in the time window of 3–12 months prior to the event were identified. At least one control was selected for each case matched for age, VL and HCV status at the time of sampling. Controls were event‐free after a matched duration of time from the date of sampling. Plasma HIV tropism was estimated using 454 and population sequencing (PS). Non‐R5 HIV was defined as: (a) ≥2% of sequences with a Geno2Pheno (G2P) FPR≤3.75% by 454, and (b) a G2P FPR≤10% by PS. We also compared CD4 slopes over the 12 months following the date of sampling using a linear mixed model with random intercept according to HIV tropism and ART status.ResultsThe study included 266 subjects, 100 cases and 166 controls, with sample taken on average in 2006; 23% and 24% had non‐R5 HIV by 454 and PS respectively. There were 19% women, 25% MSM, 92% Caucasians, 22% HCV+. At the time of sampling, 26% were ART‐naïve, 25% had started but were off ART and 49% were receiving ART. The median age, CD4 and viral load was 41 years, 350 cells/mm3 and 4.81 log c/mL, respectively. Baseline characteristics were well balanced by tropism. Factors independently associated with clinical progression or death were female gender (OR=2.12; 95% CI=1.04, 4.36; p=0.038), CD4+ count (OR=0.90 per 100 cells/mm3 higher; 95% CI 0.80, 1.00; p=0.058), being on ART (OR=2.72; 95% CI 1.15, 6.41; p=0.022) and calendar year of sample (OR=0.84 per more recent year; 95% CI=0.77, 0.91; p<0.001). Baseline plasma tropism was not an independent risk factor for clinical progression or death by either 454 or PS. No significant interaction was observed between tropism and ART status. There were no significant differences in the CD4+ slope within or between tropism groups.ConclusionsPlasma HIV‐1 tropism does not appear to add to the ability of CD4 count and viral load to predict the short term risk of AIDS and death outcomes, even with 454 sequencing.

Glycosylation of host and viral proteins is an important posttranslational modification needed to ensure correct function of glycoproteins. For this reason, we asked whether inhibition of O-glycosylation during human immunodeficiency virus (HIV) in vitro replication could affect HIV infectivity and replication rates. We used benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (BAGN), a compound that has been widely used to inhibit O-glycosylation in several cell lines. Pretreatment and culture of PHA-blast target cells with BAGN increased the percentage of HIV-infected cells (7.6-fold, p = 0.0115), the per-cell amount of HIV p24 protein (1.3-fold, p = 0.2475), and the viral particles in culture supernatants (7.1-fold, p = 0.0029) compared to BAGN-free cultures. Initiating infection with virus previously grown in the presence of BAGN further increased percentage of infected cells (30-fold, p < 0.0001), intracellular p24 (1.5-fold, p = 0.0433), and secreted viral particles (74-fold, p < 0.0001). BAGN-treated target cells showed less CD25 and CCR5 expression, but increased HLA-DR surface expression, which positively correlated with the number of infected cells. Importantly, BAGN improved viral outgrowth kinetics in 66% of the samples tested, including samples from HIV controllers and subjects in whom no virus could be expanded in the absence of BAGN. Sequencing of the isolated virus indicated no skewing of viral quasi-species populations when compared to BAGN-free culture conditions. BAGN also increased virus production in the ACH2 latency model when used together with latency-reversing agents. Taken together, our results identify BAGN treatment as a simple strategy to improve viral outgrowth in vitro and may provide novel insights into host restriction mechanisms and O-glycosylation-related therapeutic targets for HIV control strategies. ; The present study was supported by grant PI12/00529 (AO) from the Instituto de Salud Carlos III, co-financed by the Fondo Europeo de Desarrollo Regional (FEDER) "Una manera de hacer Europa" and funding from the European Union's Horizon 2020 research and innovation program under grant European AIDS Vaccine Initiative 2020 (EAVI2020) #GA681137 (CB). JM and AM were supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness and FEDER grant no. SAF2016-75505-R (AEI/MINEICO/FEDER, UE). CB and AM are senior ICREA research professors. The HIVACAT program, Foundation Dormeur, Vaduz (Liechtenstein), and an unrestricted gift by Rafael Punter, Barcelona (Spain) and the Gala SIDA 2014-2016, further supported the work.

BackgroundUse of unboosted atazanavir (ATV400) is approved in the US but not in Europe [1]. Due to pharmacokinetic interactions it should not be used with tenofovir but can be used with abacavir/lamivudine (ABC/3TC) [1, 2,3]. Effectiveness data of ATV400+ABC/3TC as a switch strategy in clinical routine however are scant.MethodsWe evaluated treatment outcomes of ATV400+ABC/3TC in pre‐treated subjects in the EuroSIDA cohort with undetectable HIV‐1 RNA, and previous ABC experience or assumed previous HLA B57*01 testing. We performed a time to loss of virologic response (TLOVR below 50 c/mL) and a snapshot analysis at 48, 96 and 144 weeks. Virological failure (VF) was defined as a confirmed plasma HIV‐1 RNA >50 c/mL.ResultsWe included 258 subjects: 176 (68%) male, median age 46 (IQR 41, 53) y, 225 (87.2%) white, hepatitis virus co‐infection 36%, median baseline CD4 at switch 540 cells (360, 700), time with VL≤ 50 c/mL 45 (24, 69) months. The median calendar year of switching was 2008 (2006, 2010). The 3rd drug in previous regimen was ATV/r in 70 (27.1%), other PI/r in 25 (9.7%), and other 163 (63.2%); 85 (32.9%) had previously failed with a PI. The virological response at 48/96/144 weeks was, respectively, 89.5 [95% CI 85.1, 92.9]/88 [83.4, 91.7]/86.3% [81.6, 90.4] (TLOVR, composite endpoint failure or stop for any reason) and the risk of VF was 8.3/7.6/7.6%. In the snapshot analysis HIV‐RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count (RH 0.60 [0.39, 0.93] per 100 cells higher), time with VL≤50 c/mL (RH 0.89 [0.81, 0.98] per 6 months longer) and previous failure with a PI (3.04 [1.36, 6.80]). There was no association with gender, age, hepatitis virus co‐infection, CD4 count at time of switching or third drug used in the previous regimen.ConclusionsA switch to ATV400+ABC/3TC in selected subjects with HIV‐RNA below 50 c/mL is associated with relatively low rates of VF and discontinuation due to adverse events. Use might be considered in those with long‐term suppression and without prior PI failure. Larger cohorts are required to further define the appropriate selection criteria.

AbstractIntroductionNext‐generation sequencing (NGS) has several advantages over conventional Sanger sequencing for HIV drug resistance (HIVDR) genotyping, including detection and quantitation of low‐abundance variants bearing drug resistance mutations (DRMs). However, the high HIV genomic diversity, unprecedented large volume of data, complexity of analysis and potential for error pose significant challenges for data processing. Several NGS analysis pipelines have been developed and used in HIVDR research; however, the absence of uniformity in data processing strategies results in lack of consistency and comparability of outputs from different pipelines. To fill this gap, an international symposium on bioinformatic strategies for NGS‐based HIVDR testing was held in February 2018 in Winnipeg, Canada, convening laboratory scientists, bioinformaticians and clinicians involved in four recently developed, publicly available NGS HIVDR pipelines. The goal of this symposium was to establish a consensus on effective bioinformatic strategies for NGS data management and its use for HIVDR reporting.DiscussionEssential functionalities of an NGS HIVDR pipeline were divided into five analytic blocks: (1) NGS read quality control (QC)/quality assurance (QA); (2) NGS read alignment and reference mapping; (3) HIV variant calling and variant QC; (4) NGS HIVDR reporting; and (5) extended data applications and additional considerations for data management. The consensuses reached among the participants on all major aspects of these blocks are summarized here. They encompass not only recommended data management and analysis strategies, but also detailed bioinformatic approaches that help ensure accuracy of the derived HIVDR analysis outputs for both research and potential clinical use.ConclusionsWhile NGS is being adopted more broadly in HIVDR testing laboratories, data processing is often a bottleneck hindering its generalized application. The proposed standardization of NGS read QC/QA, read alignment and reference mapping, variant calling and QC, HIVDR reporting and relevant data management strategies in this "Winnipeg Consensus" may serve as a starting guideline for NGS HIVDR data processing that informs the refinement of existing pipelines and those yet to be developed. Moreover, the bioinformatic strategies presented here may apply more broadly to NGS data analysis of microbes harbouring significant genomic diversity.

IntroductionIn a previous interim 24‐week virological safety analysis of the PROTEST study [1], initiation of Maraviroc (MVC) plus 2 nucleoside reverse‐transcriptase inhibitors (NRTIs) in aviremic subjects based on genotypic tropism testing of proviral HIV‐1 DNA was associated with low rates of virological failure. Here we present the final 48‐week analysis of the study.MethodsPROTEST was a phase 4, prospective, single‐arm clinical trial (ID: NCT01378910) carried on in 24 HIV care centres in Spain. Maraviroc‐naïve HIV‐1‐positive adults with HIV‐1 RNA (VL) <50 c/mL on stable ART during the previous 6 months, requiring an ART change due to toxicity, with no antiretroviral resistance to the ART started, and R5 HIV by proviral DNA genotypic tropism testing (defined as a G2P FPR >10% in a singleton), initiated MVC with 2 NRTIs and were followed for 48 weeks. Virological failure was defined as two consecutive VL>50 c/mL. Recent adherence was calculated as: (# pills taken/# pills prescribed during the previous week)*100.ResultsTropism results were available from 141/175 (80.6%) subjects screened: 87/141 (60%) were R5 and 74/87 (85%) were finally included in the study. Their median age was 48 years, 16% were women, 31% were MSM, 36% had CDC category C at study entry, 62% were HCV+ and 10% were HBV+. Median CD4+ counts were 616 cells/mm3 at screening, and median nadir CD4+ counts were 143 cells/mm3. Previous ART included PIs in 46 (62%) subjects, NNRTIs in 27 (36%) and integrase inhibitors (INIs) in 1 (2%). The main reasons for treatment change were dyslipidemia (42%), gastrointestinal symptoms (22%), and liver toxicity (15%). MVC was given alongside TDF/FTC in 40 (54%) subjects, ABC/3TC in 30 (40%), AZT/3TC in 2 (3%) and ABC/TDF in 2 (3%). Sixty‐two (84%) subjects maintained VL<50 c/mL through week 48, whereas 12 (16%) discontinued treatment: two (3%) withdrew informed consent, one (1%) had a R5→X4 shift in HIV tropism between the screening and baseline visits, one (1%) was lost to follow‐up, one (1%) developed an ART‐related adverse event (rash), two (3%) died due to non‐study‐related causes (1 myocardial infarction at week 0 and 1 lung cancer at week 36), and five (7%) developed protocol‐defined virological failure, although two of them regained VL<50 c/mL with the same MVC regimen (Table 1).ConclusionsInitiation of MVC plus 2 NRTIs in aviremic subjects based on genotypic tropism testing of proviral HIV‐1 DNA is associated with low rates of virological failure up to one year.

BACKGROUND: The BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late ( 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. METHODS: PBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone. FINDINGS: DNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion. INTERPRETATION: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. FUNDING: European Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health–National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.

Background: The BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late ( 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. Methods: PBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone. Findings: DNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion. Interpretation: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. Funding: European Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health–National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) ; Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors. ; info:eu-repo/semantics/publishedVersion

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50 years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50 years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50 years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19. ; This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202). ; Peer reviewed