Non Mycobacterial Virulence Genes in the Genome of the Emerging Pathogen Mycobacterium abscessus

Mycobacterium abscessus is an emerging rapidly growing mycobacterium (RGM) causing a pseudotuberculous lung disease to which patients with cystic fibrosis (CF) are particularly susceptible. We report here its complete genome sequence. The genome of M. abscessus (CIP 104536T) consists of a 5,067,172-bp circular chromosome including 4920 predicted coding sequences (CDS), an 81-kb full-length prophage and 5 IS elements, and a 23-kb mercury resistance plasmid almost identical to pMM23 from Mycobacterium marinum. The chromosome encodes many virulence proteins and virulence protein families absent or present in only small numbers in the model RGM species Mycobacterium smegmatis. Many of these proteins are encoded by genes belonging to a “mycobacterial” gene pool (e.g. PE and PPE proteins, MCE and YrbE proteins, lipoprotein LpqH precursors). However, many others (e.g. phospholipase C, MgtC, MsrA, ABC Fe(3+) transporter) appear to have been horizontally acquired from distantly related environmental bacteria with a high G+C content, mostly actinobacteria (e.g. Rhodococcus sp., Streptomyces sp.) and pseudomonads. We also identified several metabolic regions acquired from actinobacteria and pseudomonads (relating to phenazine biosynthesis, homogentisate catabolism, phenylacetic acid degradation, DNA degradation) not present in the M. smegmatis genome. Many of the “non mycobacterial” factors detected in M. abscessus are also present in two of the pathogens most frequently isolated from CF patients, Pseudomonas aeruginosa and Burkholderia cepacia. This study elucidates the genetic basis of the unique pathogenicity of M. abscessus among RGM, and raises the question of similar mechanisms of pathogenicity shared by unrelated organisms in CF patients

Use of rilpivirine in HIV-1 infected individuals in routine clinical practice from 2012 to 2017 in France

International audienceWe assessed virological outcomes of rilpivirine use in France from 2012 to 2017, in three groups of people living with HIV (PLHIV):(1) antiretroviral (ARV)-naïve PLHIV;(2) ARVexperienced PLHIV switching to rilpivirine while failing therapy; and (3) ARV-experienced PLHIV switching to rilpivirine while virologically controlled. Methods: Virological success (VS) was defined as a plasma HIV-1 viral load (VL)50 copies/mL or one VL>50 copies/mL followed by a treatment switch prior to the next VL measurement. The cumulative incidence of VS was assessed considering rilpivirine discontinuation, loss to follow-up, and death as competing risks, while estimates of cumulative incidence of VF accounted for loss to follow-up and death. Results: Among the 2166 ARV-naïve PLHIV initiating rilpivirine, the four-year cumulative incidence of VS was 91.0% and was associated with baseline VL. Among the 2125 ARVexperienced PLHIV switching to rilpivirine while failing therapy, the four-year cumulative incidence of VS was 82.5% and was associated with lower VL, higher CD4, and less than three prior ARVs. Among the 11828 ARV-experienced PLHIV switching to rilpivirine while virologically controlled, the four-year cumulative incidence of VF was 9.6%. The risk of VF was lower among MSM, for PLHIV with CD4≥500/mm 3 , without a prior AIDS event, or with a longer VL suppression at baseline. Conclusion: Rilpivirine-containing regimens yielded high rates of viral suppression in most participants, while it was ineffective when used outside the marketing authorization in naïve participants

Switching to Raltegravir From a Virologically Effective Boosted Protease Inhibitor Regimen: A Comparative Effectiveness Analysis From the French Hospital Database on HIV (FHDH-ANRS CO4)

For the French Hospital Database on HIV (FHDH-ANRS CO4)International audienceBackground. In individuals with viral load (VL) suppression on a boosted protease inhibitor (PI) regimen, a switch to raltegravir (RAL) can be an option in case of comorbidities, but the SWITCHMRK trials challenged this strategy. Here, among individuals with VL suppression on a boosted PI, we compared outcomes between those who continued on the same regimen and those who switched to RAL.Methods. In this cohort study from the French Hospital Database on HIV, each individual who switched to RAL was matched with up to 3 individuals who continued PI, were being followed up during the calendar period of the switch, and had the same duration of VL suppression (both ±6 months). The primary endpoint was a composite endpoint of hospitalization, or AIDS event or death, and secondary endpoints the immunovirologic responses. To control for measured confounders, the inverse probability treatment weighting (IPTW) method was applied to estimate hazards ratios between the 2 groups.Results. We matched 282 RAL switchers with 838 nonswitchers. Although several variables differed significantly between the groups, including a higher prevalence of comorbidities in the RAL group, the IPTW method yielded standardized differences <10% for all variables. After IPTW, there was no difference in the risk of hospitalization or AIDS event or death between the 2 groups (13.6% and 10.5%, respectively; hazard ratio, 1.16 [95% confidence interval, .74–1.83]) and no difference in the likelihood of virologic failure or CD4 cell gain.Conclusions. In individuals with controlled VL on a boosted PI regimen who switched to RAL, none of the endpoints differed with nonswitchers after IPTW

Simulação do fluxo de água em uma pilha de rejeito na antiga mina de uranio em Le Cellier (Lozère França)

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Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status

International audienceAntibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4 + T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with b5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r = − 0.9013; p b 0.0001), viral DNA (r = − 0.7696; p = 0.0005) and was associated the preservation of high CD4 + T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies

Durability and Effectiveness of Maraviroc-Containing Regimens in HIV-1-Infected Individuals with Virological Failure in Routine Clinical Practice

International audienceIntroductionLimited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV.MethodsVirological success was defined as VL50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25–0.70) and immunological success (HR: 0.37; 95% CI, 0.18–0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score.ConclusionIn this observational study, maraviroc-containing regimens yielded high rates of viral suppression and immunological responses in individuals with R5 viruses in whom prior regimens had failed

Structure‐based design, synthesis and biological evaluation of a NAD+ analogue targeting Pseudomonas aeruginosa NAD kinase

International audienceMulti-drug resistance is a major public health problem that requires the urgent development of new antibiotics and therefore the identification of novel bacterial targets. The activity of nicotinamide adenine dinucleotide kinase, NADK, is essential in all bacteria tested so far, including many human pathogens that display antibiotic resistance leading to failure of current treatments. Inhibiting NADK is therefore a promising and innovative antibacterial strategy since there is currently no drug on the market targeting this enzyme. Through a fragment-based drug design approach, we have recently developed a NAD+-competitive inhibitor of NADKs, which displayed in vivo activity against Staphylococcus aureus. Here we show that this compound, a di-adenosine derivative, is inactive against the NADK enzyme from the Gram-negative bacteria Pseudomonas aeruginosa (PaNADK). This lack of activity can be explained by the crystal structure of PaNADK, which was determined in complex with NADP+ in this study. Structural analysis led us to design and synthesize a benzamide adenine dinucleoside analogue, active against PaNADK. This novel compound efficiently inhibited PaNADK enzymatic activity in vitro with a Ki of 4.6 µM. Moreover, this compound reduced P. aeruginosa infection in vivo in a zebrafish model

Prevalence of and Risk Factors for Anal Oncogenic Human Papillomavirus Infection Among HIV-Infected Women in France in the Combination Antiretroviral Therapy Era

International audienceBackground. Little is known about the type-specific prevalence of anal human papillomavirus (HPV) infection and risk factors for anal high-risk (HR) HPV infection in human immunodeficiency virus (HIV)-infected women. Methods. A cross-sectional study of anal and cervical HPV infection was nested within a gynecological cohort of HIV-infected women. Specimens were tested for type-specific DNA using a polymerase chain reaction-based assay. Results. The study population consisted of 311 women with a median age of 45.3 years, of whom 42.8% originated from sub-Saharan Africa and 96.8% were receiving combination antiretroviral therapy. The median CD4 + cell count was 612/μL, and the HIV load was <50 copies/mL in 84.1%. HR-HPV types were detected in the anal canal in 148 women (47.6%) and in the cervix in 82 (26.4%). HPV-16 was the most prevalent type in both the anal canal (13.2% of women) and the cervix (5.1%). In multivariable analysis, factors associated with prevalent anal HR-HPV infection were CD4 + count <350/μL (odds ratio, 2.9; 95% confidence interval , 1.3-6.5), concurrent cervical lesions (2.6; 1.0-4.3), and cervical HR-HPV infection (1.8; 1.0-3.2). Conclusions. The high prevalence of HR-HPV types, including HPV-16, in the anal canal of HIV-positive women is concerning. Anal cancer screening should be considered for HIV-positive women as part of their routine care

Kaplan-Meier plots showing, according to R5 or non-R5 viral tropism, the times (a) to maraviroc discontinuation, (b) to a virological response VL<50 copies/ml, (c) to a sustained gain of at least 100 CD4 cells/mm³, (d) to hospitalization for a non AIDS event, an AIDS event or death.

<p>Kaplan-Meier plots showing, according to R5 or non-R5 viral tropism, the times (a) to maraviroc discontinuation, (b) to a virological response VL<50 copies/ml, (c) to a sustained gain of at least 100 CD4 cells/mm³, (d) to hospitalization for a non AIDS event, an AIDS event or death.</p