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. 2023 Sep 18:14:1213455.
doi: 10.3389/fimmu.2023.1213455. eCollection 2023.

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

Sharat Srinivasula  1 , Paula Degrange  2 , Simone Perazzolo  3 , Andrew Bonvillain  2 , Amanda Tobery  2 , Jacob Kaplan  4 , Hyukjin Jang  1 , Refika Turnier  5 , Michael Davies  5 , Mackenzie Cottrell  6 , Rodney J Y Ho  3   7 , Michele Di Mascio  4
Affiliations

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

Sharat Srinivasula et al. Front Immunol. .

Abstract

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.

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

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Physiologically-based pharmacokinetic (PBPK) modeling of TFV and its pharmacologically active moiety, TFV-dp. The model has a minimized vascular system for the eliminating organ (kidney), and the combined distributing organ (Rest-of-body, ROB). Lymph formation occurs from ROB (e.g., muscles) which drains via lymphatic capillaries to the lymphatic system. The lymphatic system was collapsed into a single representative compartment and divided into sinus and LNMC. NRTIs enter the lymph node by lymphatic circulation and through mononuclear cell migration. Inside the mononuclear cells, the NRTIs undergo kinase-mediated phosphorylation into active moieties. The trough concentrations of TFV and TFV-dp from the PBPK model simulation of a typical macaque (orange open circles for increased kinase-mediated phosphorylation rates; blue open circles for increased LNMC uptake of TFV) and the experimental observations from the 21 macaques (purple crosses) during the 3 months of antiretroviral therapy in the (B) plasma, (C) lymph node tissue, (D) peripheral blood mononuclear cells (PBMC), and (E) lymph node mononuclear cells (LNMC).
Figure 2
Figure 2
The parent antiretroviral (ARV) concentrations in (A) plasma (n=21) and (B) lymph node tissue homogenate (subgroup A, n=12 at M1 and n=13 at M3), and (C) lymph node tissue to plasma ARV ratios (subgroup A, n=12 at M1 and n=13 at M3) at months 1 and 3 of antiretroviral therapy (ART). The lymph node tissue ARV concentrations were several-fold higher than plasma ARV concentrations (P <0.005, n=12). (D) The levels of intracellular active drug metabolites (IADM) in peripheral blood mononuclear cells (PBMC, n=21) and lymph node mononuclear cells (LNMC, n=21), and (E) LNMC to PBMC IADM ratios at months 1 and 3 of ART (n=21). The IADM levels in LNMC were statistically significantly lower than in PBMC (P ≤0.005, n=21). Data were summarized with a scatter dot plot with median and interquartile range.
Figure 3
Figure 3
Associations between (A, B) plasma viremia (SIV-RNA copies/mL), (C-F) SIV-RNA levels (copies/106 cell equivalent) in lymph node tissue, or (G-J) SIV-RNA levels (copies/106 cell equivalent) in rectal tissue at the initiation of antiretroviral therapy (ART) and intracellular active drug metabolite levels (fmol/million cells) in peripheral blood mononuclear cells (PBMC) or lymph node mononuclear cells (LNMC) at one month of ART. Viral dissemination at ART initiation was generally inversely associated with intracellular active drug metabolite levels at one month into therapy.
Figure 4
Figure 4
Associations between percentage decreases of Ki67+ levels in peripheral blood CD4+ T-cells during the first month of antiretroviral therapy (ART) and (A, B) plasma antiretroviral drug concentrations, and (C, D) lymph node mononuclear cells (LNMC) intracellular active drug metabolite levels at month 1 of ART.
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