BackgroundHIV-1 is usually transmitted in the presence of semen. We have shown that semen boosts HIV-1 infection and contains fragments of prostatic acid phosphatase (PAP) forming amyloid aggregates termed SEVI (semen-derived enhancer of viral infection) that promote virion attachment to target cells. Despite its importance for the global spread of HIV-1, however, the effect of semen on virus infection is controversial.ResultsHere, we established methods allowing the meaningful analysis of semen by minimizing its cytotoxic effects and partly recapitulating the conditions encountered during sexual HIV-1 transmission. We show that semen rapidly and effectively enhances the infectivity of HIV-1, HIV-2, and SIV. This enhancement occurs independently of the viral genotype and coreceptor tropism as well as the virus producer and target cell type. Semen-mediated enhancement of HIV-1 infection was also observed under acidic pH conditions and in the presence of vaginal fluid. We further show that the potency of semen in boosting HIV-1 infection is donor dependent and correlates with the levels of SEVI.ConclusionsOur results show that semen strongly enhances the infectivity of HIV-1 and other primate lentiviruses and that SEVI contributes to this effect. Thus, SEVI may play an important role in the sexual transmission of HIV-1 and addition of SEVI inhibitors to microbicides may improve their efficacy.

Growth in biofilms as a fascinating and complex microbial lifestyle has become widely accepted as one of the key features of pathogenic microbes, to successfully express their full virulence potential and environmental persistence. This also increases the threat posed by Candida auris, which has a high intrinsic ability to persist on abiotic surfaces including those of surgical instruments and medical tubing. In a previous study, cyclic and helical-stabilized analogues of the antifungal peptide Cm-p5 were designed and synthetized, and proved to have increased activities against C. albicans and C. parapsilosis, but not against planktonic C. auris cells cultivated in suspension cultures. Here, we demonstrate, initially, that these derivatives, however, exhibited semi-inhibitory concentrations between 10–21 µg/mL toward C. auris biofilms. Maturated biofilms were also arrested between 71–97%. These novel biofilm inhibitors may open urgently needed new routes for the development of novel drugs and treatments for the next stage of fight against C. auris.

Hemoadsorption devices are used to treat septic shock by adsorbing inflammatory cytokines and as yet incompletely defined danger and pathogen associated molecular patterns. In an ideal case, hemoadsorption results in immediate recovery of microvascular endothelial cells’ (mEC) function and rapid recovery from catecholamine-dependency and septic shock. We here tested a single device, which consists of polystyrene-divinylbenzene core particles of 450 μm diameter with a high affinity for hydrophobic compounds. The current study aimed at the proof of concept that endothelial-specific damage mediators are adsorbed and can be recovered from hemoadsorption devices. Because of excellent clinical experience, we tested protein fractions released from a hemoadsorber in a novel endothelial bioassay. Video-based, long-term imaging of mEC proliferation and cell death were evaluated and combined with apoptosis and ATP measurements. Out of a total of 39 fractions recovered from column fractionation, we identified 3 fractions that caused i) inhibition of mEC proliferation, ii) increased cell death and iii) induction of apoptosis in mEC. When adding these 3 fractions to mEC, their ATP contents were reduced. These fractions contained proteins of approximately 15 kDa, and high amounts of nucleic acid, which was at least in part oxidized. The efficacy for endothelial cell damage prevention by hemoadsorption can be addressed by a novel endothelial bioassay and long-term video observation procedures. Protein fractionation of the hemoadsorption devices used is feasible to study and define endothelial damage ligands on a molecular level. The results suggest a significant effect by circulating nucleic acids – bound to an as yet undefined protein, which may constitute a major danger-associated molecular pattern (DAMP) in the exacerbation of inflammation when patients experience septic shock. Hemoadsorption devices may thus limit endothelial damage, through the binding of nucleic acid-bearing aggregates and thus contribute to improved endothelial barrier function.

The pathogenic yeast Candida auris has received increasing attention due to its ability to cause fatal infections, its resistance toward important fungicides, and its ability to persist on surfaces including medical devices in hospitals. To brace health care systems for this considerable risk, alternative therapeutic approaches such as antifungal peptides are urgently needed. In clinical wound care, a significant focus has been directed toward novel surgical (wound) dressings as first defense lines against C. auris. Inspired by Cerberus the Greek mythological “hound of Hades” that prevents the living from entering and the dead from leaving hell, the preparation of a gatekeeper hybrid hydrogel is reported featuring lectin‐mediated high‐affinity immobilization of C. auris cells from a collagen gel as a model substratum in combination with a release of an antifungal peptide drug to kill the trapped cells. The vision is an efficient and safe two‐layer medical composite hydrogel for the treatment of severe wound infections that typically occur in hospitals. Providing this new armament to the repertoire of possibilities for wound care in critical (intensive care) units may open new routes to shield and defend patients from infections and clinical facilities from spreading and invasion of C. auris and probably other fungal pathogens.

The Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a body-own fragment of albumin and specific antagonist of the CXC-motif-chemokine receptor 4 (CXCR4). CXCR4 signaling is induced by its sole chemokine ligand CXCL12 and is involved in a plethora of functions including cell homing, differentiation, survival and angiogenesis. Consequently, dysregulation of CXCR4 is involved in a variety of disorders, such as cancer or inflammatory diseases, making CXCR4 an attractive drug target. EPI-X4 and derivatives with increased CXCR4 binding affinities represent promising leads as CXCR4 antagonists and have shown therapeutic activity in mouse models of inflammatory diseases. However, it is currently unclear how EPI-X4 and its derivatives interact with CXCR4. Here, by combining biomolecular simulations with experimental mutagenesis and activity studies we investigated the binding behavior of EPI-X4 to CXCR4 at the molecular level. Our work allowed us to show that the EPI-X4 peptide interacts primarily in the minor pocket of CXCR4 through its N-terminal residues. The biomolecular interactions highlighted by the computational studies are in good agreement with the experimental mutagenesis data. Moreover, we found that the N-terminal seven amino-acids of EPI-X4 (a 16-mer) and its improved derivatives (12-mers) are sufficient for CXCR4 binding, which led to the development of shorter leads with optimized CXCR4 antagonizing properties. Collectively, we here established how EPI-X4 binds to its receptor and used this knowledge for rational drug design. The new peptide variants developed by us are more potent in terms of inhibiting CXCR4-downstream signaling and cancer cell migration, without toxic effects.