Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates

Gabriela M. Webb; Kristin A. Sauter; Diana Takahashi; Melissa Kirigiti; Lindsay Bader; Sarah R. Lindsley; Hannah M. Blomenkamp; Cicely Zaro; Molly Shallman; Casey M. McGuire; Heather Hofmeister; Uriel Avila; Cleiton Pessoa; Joseph M. Hwang; Allyson J. McCullen; Matthew Humkey; Jason Reed; Lina Gao; Lee Winchester; Courtney V. Fletcher; Oleg Varlamov; Todd T. Brown; Jonah B. Sacha; Paul Kievit; Charles T. Roberts

doi:10.1172/jci.insight.181968

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

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¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Hwang, J. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by McCullen, A. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Humkey, M. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Reed, J. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Gao, L. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Winchester, L. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Fletcher, C. in: JCI | PubMed | Google Scholar |

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Varlamov, O. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Brown, T. in: JCI | PubMed | Google Scholar |

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Sacha, J. in: JCI | PubMed | Google Scholar

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Kievit, P. in: JCI | PubMed | Google Scholar |

¹Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

²Knight Cancer Institute, Oregon Health & Science University, Beaverton, United States of America

³Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, United States of America

⁴College of Pharmacy, University of Nebraska Medical Center, Omaha, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Roberts, C. in: JCI | PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.181968.
Copyright © 2024, Webb et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published August 8, 2024 - Version history

Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving life expectancy of people living with HIV, but also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the impact of pre-existing metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4⁺ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.

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Effect of metabolic status on response to SIV infection and antiretroviral therapy in nonhuman primates

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