Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species

Corbin G. Thompson, Elias P. Rosen, Heather M.A. Prince, Nicole White, Craig Sykes, Gabriela De La Cruz, Michelle Mathews, Claire Deleage, Jacob D. Estes, Paige Charlins, Leila R. Mulder, Martina Kovarova, Lourdes Adamson, Shifali Arora, Evan S. Dellon, Anne F. Peery, Nicholas J. Shaheen, Cynthia Gay, David C. Muddiman, Ramesh AkkinaJ. Victor Garcia, Paul A Luciw, Angela D.M. Kashuba

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans). We measured drug concentrations in proximity to CD3+ T cells that are targeted by HIV, as well as expression of HIV or SHIV RNA and expression of the MDR1 drug efflux transporter in gut tissue from HIV-infected humanized mice, SHIV-infected macaques, and HIV-infected humans treated with combination antiretroviral drug therapy. Serial 10-μm sections of snap-frozen ileal and rectal tissue were analyzed by MSI for CD3+ T cells and MDR1 efflux transporter expression by immunofluorescence and immunohistochemistry, respectively. The tissue slices were analyzed for HIV/SHIV RNA expression by in situ hybridization and for antiretroviral drug concentrations by liquid chromatography-mass spectrometry. The gastrointestinal tissue distribution of the six drugs was heterogeneous. Fifty percent to 60% of CD3+ T cells did not colocalize with detectable drug concentrations in the gut tissue. In all three species, up to 90% of HIV/SHIV RNA was found to be expressed in gut tissue with no exposure to drug. These data suggest that there may be gut regions with little to no exposure to antiretroviral drugs, which may result in low-level HIV replication contributing to HIV persistence.

Original languageEnglish (US)
Article numberaap8758
JournalScience Translational Medicine
Volume11
Issue number499
DOIs
StatePublished - Jul 3 2019

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HIV
Pharmaceutical Preparations
Mass Spectrometry
Macaca
RNA
T-Lymphocytes
Frozen Sections
Tissue Distribution
Combination Drug Therapy
Liquid Chromatography
In Situ Hybridization
Fluorescent Antibody Technique
Immunohistochemistry

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thompson, C. G., Rosen, E. P., Prince, H. M. A., White, N., Sykes, C., De La Cruz, G., ... Kashuba, A. D. M. (2019). Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species. Science Translational Medicine, 11(499), [aap8758]. https://doi.org/10.1126/scitranslmed.aap8758

Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species. / Thompson, Corbin G.; Rosen, Elias P.; Prince, Heather M.A.; White, Nicole; Sykes, Craig; De La Cruz, Gabriela; Mathews, Michelle; Deleage, Claire; Estes, Jacob D.; Charlins, Paige; Mulder, Leila R.; Kovarova, Martina; Adamson, Lourdes; Arora, Shifali; Dellon, Evan S.; Peery, Anne F.; Shaheen, Nicholas J.; Gay, Cynthia; Muddiman, David C.; Akkina, Ramesh; Garcia, J. Victor; Luciw, Paul A; Kashuba, Angela D.M.

In: Science Translational Medicine, Vol. 11, No. 499, aap8758, 03.07.2019.

Research output: Contribution to journalArticle

Thompson, CG, Rosen, EP, Prince, HMA, White, N, Sykes, C, De La Cruz, G, Mathews, M, Deleage, C, Estes, JD, Charlins, P, Mulder, LR, Kovarova, M, Adamson, L, Arora, S, Dellon, ES, Peery, AF, Shaheen, NJ, Gay, C, Muddiman, DC, Akkina, R, Garcia, JV, Luciw, PA & Kashuba, ADM 2019, 'Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species', Science Translational Medicine, vol. 11, no. 499, aap8758. https://doi.org/10.1126/scitranslmed.aap8758
Thompson, Corbin G. ; Rosen, Elias P. ; Prince, Heather M.A. ; White, Nicole ; Sykes, Craig ; De La Cruz, Gabriela ; Mathews, Michelle ; Deleage, Claire ; Estes, Jacob D. ; Charlins, Paige ; Mulder, Leila R. ; Kovarova, Martina ; Adamson, Lourdes ; Arora, Shifali ; Dellon, Evan S. ; Peery, Anne F. ; Shaheen, Nicholas J. ; Gay, Cynthia ; Muddiman, David C. ; Akkina, Ramesh ; Garcia, J. Victor ; Luciw, Paul A ; Kashuba, Angela D.M. / Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species. In: Science Translational Medicine. 2019 ; Vol. 11, No. 499.
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abstract = "HIV replication within tissues may increase in response to a reduced exposure to antiretroviral drugs. Traditional approaches to measuring drug concentrations in tissues are unable to characterize a heterogeneous drug distribution. Here, we used mass spectrometry imaging (MSI) to visualize the distribution of six HIV antiretroviral drugs in gut tissue sections from three species (two strains of humanized mice, macaques, and humans). We measured drug concentrations in proximity to CD3+ T cells that are targeted by HIV, as well as expression of HIV or SHIV RNA and expression of the MDR1 drug efflux transporter in gut tissue from HIV-infected humanized mice, SHIV-infected macaques, and HIV-infected humans treated with combination antiretroviral drug therapy. Serial 10-μm sections of snap-frozen ileal and rectal tissue were analyzed by MSI for CD3+ T cells and MDR1 efflux transporter expression by immunofluorescence and immunohistochemistry, respectively. The tissue slices were analyzed for HIV/SHIV RNA expression by in situ hybridization and for antiretroviral drug concentrations by liquid chromatography-mass spectrometry. The gastrointestinal tissue distribution of the six drugs was heterogeneous. Fifty percent to 60{\%} of CD3+ T cells did not colocalize with detectable drug concentrations in the gut tissue. In all three species, up to 90{\%} of HIV/SHIV RNA was found to be expressed in gut tissue with no exposure to drug. These data suggest that there may be gut regions with little to no exposure to antiretroviral drugs, which may result in low-level HIV replication contributing to HIV persistence.",
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AU - Gay, Cynthia

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