Research ArticleHIV

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

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaap8758
DOI: 10.1126/scitranslmed.aap8758

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Insufficient exposure of tissues harboring residual HIV, including the gut, to antiretroviral drugs may contribute to HIV persistence. Thompson et al. now apply a mass spectrometry–based imaging technique to visualize the distribution of six antiretroviral drugs in gut tissue sections from two animal species (mice and macaques) and HIV-infected patients. The authors found that drug distribution was uneven throughout the gut tissue. They also found that a major proportion of gut T cells, which are targeted by HIV, did not colocalize with an antiretroviral drug. In addition, viral RNA could still be detected during drug treatment, particularly in areas of low antiretroviral drug concentrations, potentially contributing to ongoing viral replication.

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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