Reports from grant recipients 2016

Bergman Peter. Title: “Host Directed Therapy against Antimicrobial Resistant Bacteria”. Decision sum: 60 000
Summary NSCMID: We develop the concept of Host Directed Therapy, based on induction of antimicrobial peptides, and apply this principle to treat multidrug resistant bacteria.
Diarienr: 591671

Damsgaard Gunst, Jesper. Title: “The Nordic HIV-1 Latency and Cure Research Collaboration (nCURE) cohort.”. Decision sum: 65 000
Summary NSCMID: The Nordic HIV-1 Latency and Cure Research Collaboration (nCURE) cohort database has been established. Included in the nCURE cohort are individuals on ART with viral suppression for ≥18 months (one blip every two years is OK) and current CD4+ T cell counts >500 cells/μL. Hopefully the nCURE cohort will form basis for identifying HIV-1 infected patients suitable for participation in future clinical cure-related trials across the Nordic countries.
The procedure leukapheresis has been established to be used in HIV-1 infected individuals. Leukapheresis is a procedure to collect large amounts of white blood cells from the body. Leukapheresis uses a machine to separate out the different types of cells that are in the blood, removes some of the leukocytes including the peripheral blood mononuclear cells (PBMCs), and returns the other components of the blood back into the body.
The nCURE cohort has received funding from the Scandinavian Society for Antimicrobial Chemotherapy Foundation.
Diarienr: 592591

Hasman, Henrik. Title: “Characterization of carbapenemase-encoding plasmids implicated in multispecies outbreaks and interspecies spread in single patients using whole genome sequence data obtained from Nanopore MinION and Illumina MiSeq.”. Decision sum: 50 000
Summary NSCMID: This project aimed to gain knowledge and experience on assembling and comparing plasmid sequences from carbapenemase producing bacteria by using the newest sequencing technologies (combining Illumina MiSeq and Oxford Nanopore Technologies MinION sequencing). The main conclusion was that this methodological approach was to some extend feasible when combined with manually curation of plasmid sequences, but a fully automated process could not be established.
Diarienr: 588921

Hughes, Diarmaid. Title: “Interplay in the Selection of Efflux Regulatory Mutations in the Evolution of Antibiotic Resistant Bacterial Pathogens”. Decision sum: 50 000
Summary NSCMID: In the study we asked whether the spectrum of mutations in marR in ciprofloxacin-resistant clinical isolates of Escherichia coli showed evidence of selection bias, either to reduce fitness costs, or to increase drug resistance. The significant finding from this SSAC-supported study is that mutations in marR selected in ciprofloxacin-resistant clinical isolates are strongly biased against inactivating mutations. Selection favours mutant alleles that have the lowest fitness costs, even though these cause only modest reductions in drug susceptibility. This suggests that selection for high relative fitness ismore important than selection for increased resistance in determining which alleles of marR will be selected in resistant clinical isolates.
Praski Alzrigat, L., Huseby, D.L., Brandis, G. and Hughes, D. (2017) 'Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli. J. Antimicrob. Chemother. 72, 3016-3024.
Diarienr: 590481

Inghammar, Malin Title: “Serious liver side-effects of macrolide and fluoroquinolone antibiotics”. Decision sum: 60 000
Summary NSCMID: The manuscript is being finalized for submission within a few weeks. We are a bit reluctant to publish any details of the results before the manuscript is accepted for publication due to copyright issues.
Diarienr: 591701

Lennerstrand, Johan. Title: “Study of resistance in Hepatitis C virus prior to treatment with new directly acting antivirals. A Nordic Multicenter Study”. Decision sum: 60 000
Summary NSCMID: Study of resistance in Hepatitis C virus prior to treatment with new directly acting antivirals. A Nordic Multicenter Study.
Diarienr: 594761

Vibholm, Line. Title: ” Toll-like receptor 9 enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1b/2a trial: TEACH – trial 2.0”. Decision sum: 50 000
Summary NSCMID: The purpose of the study was to evaluate safety and antiviral immune response of 24 weeks administration of the TLR9 agonist Lefitolimod in HIV infected individuals. We hypothesized, that Lefitolimod augments HIV-specific CD8+ T cell cytotoxic activity and reactivates latent proviruses. This enhanced activity leads to killing of HIV-expressing cells, reducing the latent HIV-1 reservoir and increasing time to rebound.
We enrolled 14 HIV infected, cART treated individuals in a phase Ib/IIa, open label, clinical trial.
Lefitolimod was safe and well tolerated. After 24 weeks treatment, cART was withdrawn for an analytical treatment interruption. One individual, who initiated cART during chronic infection, suppressed plasma HIV RNA levels below limits of detection (20 c/mL) for 136 days. This individual did not resemble previous reports on spontaneous controllers (key characteristics of "ID 113": years of unsuccessful ART, pre-cART HIV RNA >100,000 c/mL, nadir CD4 of 29 cells/μL). Time to rebound for the remaining individuals participating in the ATI was comparable to historical data.
Immunological analyses revealed; proportions of HLA-DR/CD38+ Effector Memory (TEM) and Terminally Differentiated (TTD) CD8+ T cells increased after 12 and 24 weeks. Intracellular cytokine stain, showed a significant (p=0.0068) cohort-wide increase in IFN-γ response in HIV-specific CD8+ T Effector Memory (TEM) cells from baseline to after 24 weeks treatment. "ID 113" had the highest percentage of polyfunctional HIV-specific CD8+ TEM (double positive IFN-γ+/TNF-α+ and triple positive IL-2+/IFN-γ+/TNF-α+) which further increased 3-fold from baseline to end of treatment, indicating that polyfunctional HIV-specific CD8+ T cells might have contributed to the observed virological control.
In conclusion: Lefitolimod was safe, enhanced HIV-specific CD8+ TEM cell responses, allowed us to observe increased time to rebound in an individual with strong polyfunctional HIV-specific CD8+ TEM responses.
Diarienr: 593951