{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:08:36Z","timestamp":1790705316968,"version":"4.1.0"},"reference-count":62,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Int AIDS Soc."],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4<jats:sup>+<\/jats:sup> T cells and cell\u2010associated RT\u2010SHIV viral RNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Between December 2014 and April 2017, RT\u2010SHIV infected (SHIV+; <jats:italic>N<\/jats:italic> = 6) and healthy (SHIV\u2013; <jats:italic>N<\/jats:italic> = 6) male rhesus macaques received two selected four\u2010drug combinations of six ARVs over 10 days to attain steady\u2010state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4<jats:sup>+<\/jats:sup> T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co\u2010registered images using MATLAB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Through MSI, ARV\u2010dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5\u20136 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2\u20131.4] mm; SHIV\u2013: 1.3 [0.5\u20131.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen\u2010wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94\u20132.69] \u2010fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (<jats:italic>p<\/jats:italic> = 0.03). Median co\u2010localization of drug with CD4<jats:sup>+<\/jats:sup> target cells and vRNA varied widely by ARV (5.1\u2013100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell\u2010associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low\u2010level viral replication during suppressive ART.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.25895","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T02:05:47Z","timestamp":1650420347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Antiretroviral drug exposure in lymph nodes is heterogeneous and drug dependent"],"prefix":"10.1002","volume":"25","author":[{"given":"Elias P.","family":"Rosen","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Deleage","sequence":"additional","affiliation":[{"name":"AIDS and Cancer Virus Program Frederick National Laboratory for Cancer Research Leidos Biomedical Research, Inc.  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"White","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Sykes","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Brands","sequence":"additional","affiliation":[{"name":"AIDS and Cancer Virus Program Frederick National Laboratory for Cancer Research Leidos Biomedical Research, Inc.  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Adamson","sequence":"additional","affiliation":[{"name":"Department of Pathology Microbiology &amp; Immunology School of Veterinary Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Luciw","sequence":"additional","affiliation":[{"name":"Department of Pathology Microbiology &amp; Immunology School of Veterinary Medicine University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob D.","family":"Estes","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute Oregon Health &amp; Science University  Beaverton Oregon USA"},{"name":"Oregon National Primate Research Center Oregon Health &amp; Science University  Beaverton Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela D. 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