Adipocytes impair efficacy of antiretroviral therapy

Jacob Couturier, Lee C. Winchester, James W. Suliburk, Gregory K. Wilkerson, Anthony T. Podany, Neeti Agarwal, Corrine Ying Xuan Chua, Pramod N. Nehete, Bharti P. Nehete, Alessandro Grattoni, K. Jagannadha Sastry, Courtney V. Fletcher, Jordan E. Lake, Ashok Balasubramanyam, Dorothy E. Lewis

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue.

Original languageEnglish (US)
Pages (from-to)140-148
Number of pages9
JournalAntiviral Research
Volume154
DOIs
StatePublished - Jun 2018

Keywords

  • Adipose tissue
  • Antiretroviral therapy
  • CD4 T cells
  • Dolutegravir
  • HIV reservoirs
  • Tenofovir

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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