Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 65, Issue 6, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00019-21
Keywords
antiretroviral agents; drug distribution; human immunodeficiency virus; mass spectrometry
Categories
Funding
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [R01 AI111891, R01 AI143411-01A1, R01 AI149672]
- University of North Carolina at Chapel Hill Center for AIDS Research (UNC CFAR) grant [P30 AI50410]
- Bill and Melinda Gates Foundation [INV-002704]
- [P51 OD011107]
- [P51 OD011092]
- Bill and Melinda Gates Foundation [INV-002704] Funding Source: Bill and Melinda Gates Foundation
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Our study found that a significant portion of mesenteric lymph node tissue was not covered by any antiretroviral drugs, and a substantial amount of FDC-trapped virions and infected cells were not exposed to detected ARVs. While cumulative antiretroviral therapy coverage was high, a large portion of tissue coverage was from only one ARV, mainly maraviroc. Collagen deposition did not influence the heterogeneity of ARV distribution. Our findings suggest that ARV distribution, in addition to total-tissue drug concentration, is important when evaluating viral persistence in lymph nodes and other reservoir tissues.
Human immunodeficiency virus (HIV) persistence in tissue reservoirs is a major barrier to HIV cure. While antiretrovirals (ARVs) suppress viral replication, anti-retroviral therapy (ART) interruption results in rapid rebound viremia that may originate from lymphoid tissues. To understand the relationship between anatomic distribution of ARV exposure and viral expression in lymph nodes, we performed mass spectrometry imaging (MSI) of 6 ARVs, RNAscope in situ hybridization for viral RNA (vRNA), and immunohistochemistry of collagen in mesenteric lymph nodes from 8 uninfected and 10 reverse transcriptase simian/human immunodeficiency virus (RT-SHIV)-infected rhesus macaques dosed to steady state with combination ART. MATLAB-based quantitative imaging analysis was used to evaluate spatial and pharmacological relationships between these ARVs, viral RNA (both vRNA(+) cells and follicular dendritic cell [FDC]-bound virions), and collagen deposition. Using MSI, 31% of mesenteric lymph node tissue area was found to be not covered by any ARV. Additionally, 28% of FDC-trapped virions and 21% of infected cells were not exposed to any detected ARV. Of the 69% of tissue area that was covered by cumulative ART exposure, nearly 100% of concentrations were greater than in vitro 50% inhibitory concentration (IC50) values; however, 52% of total tissue coverage was from only one ARV, primarily maraviroc. Collagen covered similar to 35% of tissue area but did not influence ARV distribution heterogeneity. Our findings are consistent with our hypothesis that ARV distribution, in addition to total-tissue drug concentration, must be considered when evaluating viral persistence in lymph nodes and other reservoir tissues.
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