The grey mould fungus Botrytis cinerea causes losses of commercially important fruits, vegetables and ornamentals worldwide. Fungicide treatments are effective for disease control, but bear the risk ...of resistance development. The major resistance mechanism in fungi is target protein modification resulting in reduced drug binding. Multiple drug resistance (MDR) caused by increased efflux activity is common in human pathogenic microbes, but rarely described for plant pathogens. Annual monitoring for fungicide resistance in field isolates from fungicide-treated vineyards in France and Germany revealed a rapidly increasing appearance of B. cinerea field populations with three distinct MDR phenotypes. All MDR strains showed increased fungicide efflux activity and overexpression of efflux transporter genes. Similar to clinical MDR isolates of Candida yeasts that are due to transcription factor mutations, all MDR1 strains were shown to harbor activating mutations in a transcription factor (Mrr1) that controls the gene encoding ABC transporter AtrB. MDR2 strains had undergone a unique rearrangement in the promoter region of the major facilitator superfamily transporter gene mfsM2, induced by insertion of a retrotransposon-derived sequence. MDR2 strains carrying the same rearranged mfsM2 allele have probably migrated from French to German wine-growing regions. The roles of atrB, mrr1 and mfsM2 were proven by the phenotypes of knock-out and overexpression mutants. As confirmed by sexual crosses, combinations of mrr1 and mfsM2 mutations lead to MDR3 strains with higher broad-spectrum resistance. An MDR3 strain was shown in field experiments to be selected against sensitive strains by fungicide treatments. Our data document for the first time the rising prevalence, spread and molecular basis of MDR populations in a major plant pathogen in agricultural environments. These populations will increase the risk of grey mould rot and hamper the effectiveness of current strategies for fungicide resistance management.
The micrographic phytopathogen Botrytis cinerea causes gray mold diseases in a large number of dicotyledonous crop plants and ornamentals. Colonization of host tissue is accompanied by rapid killing ...of plant cells ahead of the growing hyphen, probably caused by secretion of nonspecific phytotoxins, e.g., the sesquiterpene botrydial. Although all pathogenic strains tested so far had been shown to secrete botrydial and although the toxin causes comparable necrotic lesions as infection by the fungus, the role of botrydial in the infection process has not been elucidated so far. Here, we describe the functional characterization of bcbot1, encoding a P450 monooxygenase and provide evidence that it is involved in the botrydial pathway, i.e., it represents the first botrydial biosynthetic gene identified. We show that bcbot1 is expressed in planta and that expression in vitro and in planta is controlled by an alpha-subunit of a heterotrimeric GTP-binding protein, BCG1. Deletion of bcbot1 in three standard strains of B. cinerea shows that the effect on virulence (on several host plants) is strain-dependent; only deletion in one of the strains (T4) led to reduced virulence.
Integrase strand transfer inhibitors (INSTIs) are increasingly used in patients living with HIV due to their safety, effectiveness and high genetic barrier. However, an association with weight gain ...has recently been suggested and several cases of diabetes mellitus have been reported with raltegravir and dolutegravir. The long-time metabolic impact of these recent molecules remains unclear.
To assess if an INSTI as a third agent is statistically associated with new-onset diabetes mellitus compared with an NNRTI or a PI.
Patients undergoing first-line combined ART (cART) without diabetes at baseline were retrospectively included from the Dat'AIDS French cohort study (ClinicalTrials.gov NCT02898987). Incident diabetes mellitus was defined as a notification of new diabetes in the medical history, a glycated haemoglobin (HbA1c) level superior to 7.5% or the start of a diabetes therapy following the initiation of ART.
From 2009 to 2017, 19 462 patients were included, among which 265 cases of diabetes mellitus occurred. Multivariate and survival analyses did not highlight an increase in new-onset diabetes in patients undergoing cART with an INSTI as a third agent compared with an NNRTI or a PI. BMI >30 kg/m2, age >37 years old (in survival analysis), black race or Hispanic ethnicity, arterial hypertension and AIDS were associated with a higher proportion of incident diabetes.
INSTIs were not statistically associated with new-onset diabetes. However, clinicians should remain aware of this possible metabolic comorbidity, particularly in patients with a high BMI and older patients.
Abstract
Background
Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy ...(ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear.
Methods
We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality.
Results
CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 95% confidence interval {CI }1.10–6.19 and 2.03 95% CI 1.24–3.33, respectively). CD4 cell counts below 350 cells/μL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies.
Conclusions
In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.
Low CD4:CD8 ratios are independently of CD4 cell counts associated with increased risk of AIDS-defining and infection-related malignancies in antiretroviral-treated people with human immunodeficiency virus (HIV). Combined with cancer screening strategies, markers' monitoring could benefit individuals wiht inadequate immunological reconstitution.
Botrytis cinerea is responsible for the gray mold disease on more than 200 host plants. This necrotrophic ascomycete displays the capacity to kill host cells through the production of toxins, ...reactive oxygen species and the induction of a plant-produced oxidative burst. Thanks to an arsenal of degrading enzymes, B. cinerea is then able to feed on different plant tissues. Recent molecular approaches, for example on characterizing components of signal transduction pathways, show that this fungus shares conserved virulence factors with other phytopathogens, but also highlight some Botrytis-specific features. The discovery of some first strain-specific virulence factors, together with population data, even suggests a possible host adaptation of the strains. The availability of the genome sequence now stimulates the development of high-throughput functional analysis to decipher the mechanisms involved in the large host range of this species.
Aspirational targets to end AIDS by 2030 include having 95% of people with human immunodeficiency virus (HIV; PWH) diagnosed, 95% treated, and 95% with controlled viral load (VL). Our objective was ...to describe, using a large French prospective cohort, the median transition times through the cascade of care between 2009 and 2019.
We analyzed patients whose first HIV diagnosis was made between 1 January 2009 and 31 December 2019. Using the Kaplan-Meier method, we estimated the time to linkage to care (from HIV diagnosis to first biological assessment), to treatment (date of first antiretroviral therapy ART prescription), and to controlled VL (first value <200 copies/mL). Analyses were disaggregated by time periods and patients' characteristics. Censoring date was 31 December 2021.
Among the 16 864 patients linked to care since 2009, the median Q1; Q3 time from HIV diagnosis to controlled VL decreased from 254 127-745 to 73 48-132 days in 2009-2011 and 2018-2019, respectively. Transition times from linkage to care to first ART decreased from 67 17; 414 in 2009-2011 to 13 5; 26 days in 2018-2019, and from ART to controlled VL from 83 35; 130 in 2009-2011 to 38 28; 90 days in 2018-2019. Differences were observed depending on patients' characteristics.
We describe drastic reductions in transition time through the cascade of care, allowing reduction in the transmission period following each new infection. Delayed diagnosis remains the main obstacle to ending AIDS in the next decade.
Abstract
Objectives
To analyse the occurrence of virological failure (VF) in patients starting ART with an integrase strand transfer inhibitor (INSTI)-based regimen in recent years, in relation with ...previous episodes of low-level viral load (LLVL).
Patients and methods
Patients starting a first ART between 1 January 2015 and 31 December 2020 based on two NRTIs and one INSTI were included if after virological control (two measures of VL < 50 copies/mL) they had a minimum of two additional VL measurements. Cox models adjusted for sex, age, acquisition group, hepatitis B or C coinfection, place of birth, year of ART initiation, CD4+ T cells and VL at ART initiation, duration of known HIV infection and of ART regimen were used to assess the association between the time to VF and the occurrence of LLVL. ART regimen was evaluated as time-varying covariate.
Results
LLVL was described in 13.7% and VF in 11% of the 3302 patients. LLVL was associated with VF adjusted HR (aHR) 1.76, 95% CI 1.28–2.41, as well as age (aHR 0.97/year, 95% CI 0.96–0.98), CD4+ T cell count at ART initiation (aHR 0.93, 95% CI 0.87–0.98), heterosexual transmission (aHR 1.76, 95% CI 1.30–2.37) and being born abroad (aHR 1.50, 95% CI 1.17–1.93).
Conclusions
LLVL was related to VF. Even in the absence of subsequent failure, LLV episodes have a cost. Thus any VL value above 50 copies/mL should lead to enhanced adherence counselling.
The EuroSIDA study was initiated in 1994 and follows adult people living with HIV (PLHIV) in 100 collaborating clinics across 35 countries covering all European regions, Israel and Argentina. The ...study aims to study the long‐term virological, immunological and clinical outcomes of PLHIV and to monitor temporal changes and regional differences in outcomes across Europe. Annually collected data include basic demographic characteristics, information on AIDS‐ and non‐AIDS‐related clinical events, and details about antiretroviral therapy (ART), hepatitis C treatment and other medications, in addition to a range of laboratory values. The summer 2016 data set held data from a total of 23 071 individuals contributing 174 481 person‐years of follow‐up, while EuroSIDA’s unique plasma repository held over 160 000 samples. Over the past 25 years, close to 300 articles have been published in peer‐reviewed journals (h‐index 52), covering a range of scientific focus areas, including monitoring of clinical and virological outcomes, ART uptake, efficacy and adverse events, the influence of hepatitis virus coinfection, variation in the quality of HIV care and management across settings and regions, and biomarker research. Recognizing that there remain unresolved issues in the clinical care and management of PLHIV in Europe, EuroSIDA was one of the cohorts to found The International Cohort Consortium of Infectious Disease (RESPOND) cohort consortium on infectious diseases in 2017. In celebration of the EuroSIDA study’s 25th anniversary, this article aims to summarize key scientific findings and outline current and future scientific focus areas.
Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and ...follow-up.
We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF.
Between 2014 and 2018, all HIV-1-infected adults included in the Dat'AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF.
We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11-31) and 19 months (IQR = 11-31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28-6.93). No factor was associated with VF on dolutegravir/xTC.
In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy.
Abstract
Background
Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus.
Methods
Antiretroviral ...treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression.
Results
Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years interquartile range, 46.7–59.0 vs 47.7 39.7–54.3), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate IR 22.5/1000 PYFU; 95% confidence interval CI: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53).
Conclusions
This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.
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