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

Introduction and methods: To 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. Results: The 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. Conclusion: These 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.

Monitoring Immune Activation with Whole-Body Fluorodeoxyglucose-Positron-Emission Tomography in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

This study aimed to assess immune activation in tissues by measuring glucose metabolism with 18F-fluorodeoxyglucose (FDG) and investigate the associations of various peripheral markers of disease progression with initiation and interruption of combination antiretroviral therapy in SIV-infected rhesus macaques (Macaca mulatta). Mixed-effect linear models revealed a significant inverse association of peripheral blood CD4+ T cell counts (p < 0.01) and a direct association of plasma viral load (p < 0.01) with the FDG uptake in the spleen, bone marrow, and most clusters of lymph nodes. In contrast, no significant associations were found for the liver and the bowel FDG uptake. We also found no association of the fraction of proliferating peripheral blood T and B lymphocytes with FDG uptake in any analyzed tissues. The bowel FDG uptake of uninfected animals was heterogeneous and reached levels as high as those seen in the bowel or the clusters of lymph nodes or the spleen of high viremic SIV-infected animals, suggesting that factors beyond SIV-induced immune activation dominate the gut FDG uptake.

Systemic administration of the potential countermeasure huperzine reversibly inhibits central and peripheral acetylcholinesterase activity without adverse cognitive-behavioral effects.

Huperzine A is potentially superior to pyridostigmine bromide as a pretreatment for nerve agent intoxication because it inhibits acetylcholinesterase both peripherally and centrally, unlike pyridostigmine, which acts only peripherally. Using rhesus monkeys, we evaluated the time course of acetylcholinesterase and butyrylcholinesterase inhibition following four different doses of -(-)huperzine A: 5, 10, 20, and 40 microg/kg. Acetylcholinesterase inhibition peaked 30 min after intramuscular injection and varied dose dependently, ranging from about 30% to 75%. Subsequently, cognitive-behavioral functioning was also evaluated at each dose of huperzine A using a six-item serial-probe recognition task that assessed attention, motivation, and working memory. Huperzine did not impair performance, but physostigmine did. The results demonstrate that huperzine A can selectively and reversibly inhibit acetylcholinesterase without cognitive-behavioral side effects, thus warranting further study.