Background: In patients with HIV/AIDS receiving antiretroviral therapy (ART), HIV-1 persistence in brain tissue is a vital and unanswered question. HIV-1 infects and replicates in resident microglia and trafficking macrophages within the brain although the impact of individual ART drugs on viral infection within these brain myeloid cells is unknown. Herein, the effects of contemporary ART drugs were investigated using in vitro and in vivo models of HIV-1 brain infection.
Results: The EC values for specific ART drugs in HIV-infected human microglia were significantly higher compared to bone marrow-derived macrophages and peripheral blood mononuclear cells. Intracellular ART drug concentrations in microglia were significantly lower than in human lymphocytes. In vivo brain concentrations of ART drugs in mice were 10 to 100-fold less in brain tissues compared with plasma and liver levels. In brain tissues from untreated HIV-infected BLT mice, HIV-encoded RNA, DNA and p24 were present in human leukocytes while ART eradicated viral RNA and DNA in both brain and plasma. Interruption of ART resulted in detectable viral RNA and DNA and increased human CD68 expression in brains of HIV-infected BLT mice. In aviremic HIV/AIDS patients receiving effective ART, brain tissues that were collected within hours of last ART dosing showed HIV-encoded RNA and DNA with associated neuroinflammatory responses.
Conclusions: ART drugs show variable concentrations and efficacies in brain myeloid cells and tissues in drug-specific manner. Despite low drug concentrations in brain, experimental ART suppressed HIV-1 infection in brain although HIV/AIDS patients receiving effective ART had detectable HIV-1 in brain. These findings suggest that viral suppression in brain is feasible but new approaches to enhancing ART efficacy and concentrations in brain are required for sustained HIV-1 eradication from brain.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644262 | PMC |
| http://dx.doi.org/10.1186/s12977-017-0370-5 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Global longitudinal strain as an early marker of cardiac damage after cardiotoxic medications, a state of the art review.
Prog Cardiovasc Dis
January 2025
Department of Internal Medicine, Section on Internal Medicine C, University of Verona, Italy. Electronic address:
Ejection fraction (EF) is the principal parameter used clinically to assess cardiac function and provides prognostic information. However, significant myocardial damage can be present despite preserved EF. Recently, the measurement of left ventricle (LV) deformation by global longitudinal strain (GLS) has been introduced as a novel early marker of cardiac dysfunction.
View Article and Find Full Text PDFSP-DTI: Subpocket-Informed Transformer for Drug-Target Interaction Prediction.
Bioinformatics
January 2025
School of Engineering, Westlake University, Hangzhou, 310024, China.
Motivation: Drug-target interaction (DTI) prediction is crucial for drug discovery, significantly reducing costs and time in experimental searches across vast drug compound spaces. While deep learning has advanced DTI prediction accuracy, challenges remain: (i) existing methods often lack generalizability, with performance dropping significantly on unseen proteins and cross-domain settings; (ii) current molecular relational learning often overlooks subpocket-level interactions, which are vital for a detailed understanding of binding sites.
Results: We introduce SP-DTI, a subpocket-informed transformer model designed to address these challenges through: (i) detailed subpocket analysis using the Cavity Identification and Analysis Routine (CAVIAR) for interaction modeling at both global and local levels, and (ii) integration of pre-trained language models into graph neural networks to encode drugs and proteins, enhancing generalizability to unlabeled data.
Hepatotoxicity in Cancer Immunotherapy: Diagnosis, Management, and Future Perspectives.
Cancers (Basel)
December 2024
Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milano, Italy.
Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis.
View Article and Find Full Text PDFBrief Report: Stated Preferences for Long-Acting Injectable ART Among Mobile Men Living With HIV in Malawi: A Qualitative Study.
J Acquir Immune Defic Syndr
December 2024
Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; and.
Background: Long-acting injectable (LAI) antiretroviral medications are as effective as daily oral antiretroviral therapy (ART) and offer discreet, less frequent dosing. LAIs may be ideal treatment options for people who experience challenges with adherence to daily oral ART, including mobile men living with HIV (MLHIV).
Methods: We conducted a qualitative substudy within two parent trials in 24 health facilities in Malawi that enrolled MLHIV ≥15 years not on ART.
CCR5-ligand decorated rilpivirine lipid-based nanoparticles for sustained antiretroviral responses.
Nat Commun
January 2025
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Antiretroviral therapy (ART) improves the quality of life for those living with the human immunodeficiency virus type one (HIV-1). However, poor compliance reduces ART effectiveness and leads to immune compromise, viral mutations, and disease co-morbidities. Here we develop a drug formulation in which a lipid-based nanoparticle (LBNP) carrying rilpivirine (RPV) is decorated with the C-C chemokine receptor type 5 (CCR5) targeting peptide.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!