- Confirmed microsporidial graft infection in a hiv-negative renal transplant recipient: a case report and review of the literature. [Case Reports]
- TITranspl Infect Dis 2018 Mar 23; :e12888
- Microsporidia are intracellular organisms most commonly known to cause opportunistic infection in patients with human immunodeficiency virus (HIV). There have been several case reports of infection i...
Microsporidia are intracellular organisms most commonly known to cause opportunistic infection in patients with human immunodeficiency virus (HIV). There have been several case reports of infection in solid organ and bone marrow transplant recipients. Here, we report a case of a non-HIV-infected renal transplant patient with microsporidiosis of the renal tract associated with acute graft dysfunction. We also review the literature of twelve previously reported cases of microsporidiosis in patients with renal transplants who had described graft involvement. We review the pattern of illness as well as the common renal biopsy features when microsporidial infection is associated with renal graft infection. This article is protected by copyright. All rights reserved.
- Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design. [Journal Article]
- JLJ Leukoc Biol 2018 Mar 23
- The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4 also known as fusin or CD184 (cluster of differentiation 184)) is implicated in various biological and pathological processes of the hema...
The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4 also known as fusin or CD184 (cluster of differentiation 184)) is implicated in various biological and pathological processes of the hematopoietic and immune systems. CXCR4 is also one of the major coreceptors for HIV-1 entry into target cells and is overexpressed in many cancers, supporting cell survival, proliferation, and migration. CXCR4 is thus an extremely relevant drug target. Among the different strategies to block CXCR4, chemokine-derived peptide inhibitors hold great therapeutic potential. In this study, we used the N-terminus of vCCL2/vMIPII, a viral CXCR4 antagonist chemokine, as a scaffold motif to engineer and select CXCR4 peptide inhibitors, called Mimokines, which imitate the chemokine-binding mode but display an enhanced receptor affinity, antiviral properties, and receptor selectivity. We first engineered a Mimokine phage displayed library based on the first 21 residues of vCCL2, in which cysteine 11 and 12 were fully randomized and screened it against purified CXCR4 stabilized in liposomes. We identified Mimokines displaying up to 4-fold higher affinity for CXCR4 when compared to the reference peptide and fully protected MT-4 cells against HIV-1 infection. These selected Mimokines were then subjected to dimerization, D-amino acid, and aza-β3-amino acid substitution to further enhance their potency and selectivity. Optimized Mimokines exhibited up to 120-fold enhanced CXCR4 binding (range of 20 nM) and more than 200-fold improved antiviral properties (≤ 1 μM) compared to the parental Mimokines. Interestingly, these optimized Mimokines also showed up to 25-fold weaker affinity for ACKR3/CXCR7 and may therefore serve as lead compounds for further development of more selective CXCR4 peptide inhibitors and probes.
- The roles of resident, central and effector memory CD4 T cells in protective immunity following infection or vaccination. [Review]
- IImmunology 2018 Mar 23
- Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T cells play a central role in all adaptive immune responses. Vaccines must, t...
Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include HIV, tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T cells we need to understand how memory CD4 T cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T cells that are found in peripheral tissues (tissue resident memory T cells) and in the circulation (central and effector memory T cells). We discuss the generation of these cells and the evidence that demonstrates how they provide immune protection in animal and human challenge models. This article is protected by copyright. All rights reserved.
- Implementing parallel spreadsheet models for health policy decisions: The impact of unintentional errors on model projections. [Journal Article]
- PlosPLoS One 2018; 13(3):e0194916
- CONCLUSIONS: Standard error-checking techniques may not identify all errors in spreadsheet-based models. Comparing parallel model versions can aid in identifying unintentional errors and promoting reliable model projections, particularly when resources are limited.
- HIV treatment eligibility expansion and timely antiretroviral treatment initiation following enrollment in HIV care: A metaregression analysis of programmatic data from 22 countries. [Journal Article]
- PMPLoS Med 2018; 15(3):e1002534
- CONCLUSIONS: These findings underscore the potential of ART eligibility expansion to improve the timeliness of ART initiation globally, particularly for young adults.
- When do coinfections matter? [Journal Article]
- COCurr Opin Infect Dis 2018 Mar 22
- CONCLUSIONS: Tackling these challenges, using animal models, or careful prospective studies in humans may prove to be worthwhile. There are already tantalizing examples where identification and treatment of relevant coinfections seems to hold promise for improved health outcomes.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.
- Retention and adherence: global challenges for the long-term care of adolescents and young adults living with HIV. [Journal Article]
- COCurr Opin HIV AIDS 2018 Mar 22
- CONCLUSIONS: There is an urgent need for evidence-based interventions addressing gaps in the adolescent HIV care cascade, including supporting retention in care and adherence to ART.
- Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. [Journal Article]
- JCJ Chem Theory Comput 2018 Mar 23
- Water is an essential in many biological processes, and the hydration structure plays a critical role in facilitating protein folding, dynamics and ligand binding. A variety of biophysical spectrosco...
Water is an essential in many biological processes, and the hydration structure plays a critical role in facilitating protein folding, dynamics and ligand binding. A variety of biophysical spectroscopic techniques have been used to probe the water solvating proteins, often complemented with molecular dynamics (MD) simulations to resolve the spatial and dynamic features of the hydration shell, but comparing relative water structure is challenging. In this study 1 microsecond MD simulations were performed to identify and characterize hydration sites around HIV-1 protease bound to an inhibitor, darunavir (DRV). The water density, hydration site occupancy, extent and anisotropy of fluctuations, coordinated water molecules, and hydrogen bonds were characterized and compared to the properties of bulk water. The water density of the principal hydration shell was found to be higher than bulk, dependent on the topology and physio-chemical identity of the biomolecular surface. The dynamics of water molecules occupying principal hydration sites was highly dependent on the number of water-water interactions, and inversely correlated with hydrogen bonds to the protein-inhibitor complex. While many waters were conserved following the symmetry of homodimeric HIV protease, the asymmetry induced by DRV resulted in asymmetric lower-occupancy hydration sites at the concave surface of the active site. Key interactions between water molecules and the protease, that stabilize the protein in the inhibited form, were altered in a drug resistant variant of the protease indicating that modulation of solvent-solute interactions might play a key role in conveying drug resistance. Our analysis provides insights into the interplay between an enzyme inhibitor complex and the hydration shell and has implications in elucidating water structure in a variety of biological processes and applications including ligand binding, inhibitor design and resistance.
- ANIONIC CARBOSILANE DENDRIMERS DESTABILIZE THE GP120-CD4 COMPLEX BLOCKING HIV-1 ENTRY AND CELL TO CELL FUSION. [Journal Article]
- BCBioconjug Chem 2018 Mar 23
- Cell-to-cell transmission is the most effective pathway for human immunodeficiency virus (HIV-1) spread. Infected cells expose virus-encoded fusion proteins on their surface as consequence of HIV-1 r...
Cell-to-cell transmission is the most effective pathway for human immunodeficiency virus (HIV-1) spread. Infected cells expose virus-encoded fusion proteins on their surface as consequence of HIV-1 replicative cycle that interacts with non-infected cells through CD4 receptor and CXCR4 co-receptor leading to the formation of giant multinucleated cells known as syncytia. Our group previously described the potent activity of dendrimers against R5-tropic viruses. Nevertheless, the study of G1-S4, G2-S16 and G3-S16 dendrimers in the context of X4-HIV-1 tropic cell-cell fusion referred to syncytium formation remains still unknown. These dendrimers showed a suitable biocompatibility in all cell lines studied and our results demonstrated that anionic carbosilane dendrimers G1-S4, G2-S16 and G3-S16 significantly inhibit the X4-HIV-1 infection, as well as syncytia formation, in a dose dependent manner. We also demonstrated that G2-S16 and G1-S4 reduced significantly syncytia formation in HIV-1 Env-mediated cell-to-cell fusion model. Molecular modeling and in silico models showed that G2-S16 dendrimer interfered with gp120-CD4 complex and demonstrated its potential use for a treatment.
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- Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections: Promises and Perils. [Journal Article]
- AIACS Infect Dis 2018 Mar 23
- Despite their high global incidence, sexually transmitted infections (STIs) remain a neglected area of research. Increased rates of STIs have been reported in particular among men who have sex with m...
Despite their high global incidence, sexually transmitted infections (STIs) remain a neglected area of research. Increased rates of STIs have been reported in particular among men who have sex with men (MSM) probably because of the advances in the treatment and prophylaxis of human immunodeficiency virus (HIV) infection with a decrease in condom use. A recent report among MSM showed that the use of postexposure prophylaxis with doxycycline could dramatically reduce the incidence of chlamydia and syphilis but not of gonorrhea. The long-term consequences of this strategy are yet unknown, especially the risk of selection and dissemination of syphilis and chlamydia strains with doxycycline resistance, which has not been reported yet.