Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques

Frontiers in Immunology

Immunology

Amanda Tobery¹  Paula Degrange¹  Andrew Bonvillain¹  Sharat Srinivasula²  Hyukjin Jang²  Jacob Kaplan³  Michele Di Mascio³  Michael Davies⁴  Refika Turnier⁴  Simone Perazzolo⁵  Rodney J. Y. Ho⁶  Mackenzie Cottrell⁷ 

[1] AIDS Imaging Research Section, Charles River Laboratories, Integrated Research Facility, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Frederick, MD, United States;AIDS Imaging Research Section, Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, United States;AIDS Imaging Research Section, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Poolesville, MD, United States;Clinical Support Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United States;Department of Pharmaceutics, University of Washington, Seattle, WA, United States;Department of Pharmaceutics, University of Washington, Seattle, WA, United States;Department of Bioengineering, University of Washington, Seattle, WA, United States;Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, United States;

关键词: SIV infection;    lymph nodes;    immune activation;    drug metabolite;    rhesus macaque;    tenofovir;    pharmacokinetic model;    antiretroviral therapy (ART);   

DOI  :  10.3389/fimmu.2023.1213455

 received in 2023-05-02, accepted in 2023-09-01,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction and methodsTo understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months.ResultsThe intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments.ConclusionThese observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.

【 授权许可】

Unknown   
Copyright © 2023 Srinivasula, Degrange, Perazzolo, Bonvillain, Tobery, Kaplan, Jang, Turnier, Davies, Cottrell, Ho and Di Mascio