Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Virol. Aug 12, 2017; 6(3): 53-58
Published online Aug 12, 2017. doi: 10.5501/wjv.v6.i3.53
Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes
Eyone Jones, Pavel Mazirka, Margaret A McNurlan, Frank Darras, Marie C Gelato, Giuseppe Caso
Eyone Jones, Department of Surgery, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States
Pavel Mazirka, Margaret A McNurlan, Giuseppe Caso, Department of Surgery, Stony Brook University Medical Center, Stony Brook, NY 11794, United States
Frank Darras, Department of Urology, Stony Brook University Medical Center, Stony Brook, NY 11794, United States
Marie C Gelato, Department of Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, United States
Author contributions: Jones E contributed to data collection; McNurlan MA contributed to study design; Darras F recruited study subjects, collected surgical samples, and contributed to drafting the manuscript; Gelato MC contributed to overall study design; Caso G contributed to study design, performed the experiments; Jones E, Mazirka P, McNurlan MA and Caso G contributed to data analysis; Jones E, Mazirka P, McNurlan MA, Gelato MC and Caso G writing of the manuscript; Jones E, McNurlan MA, Gelato MC and Caso G contributed to data interpretation; all authors approved the final version of the manuscript.
Institutional review board statement: The study was reviewed and approved by the Stony Brook University Institutional Review Board. All specimens were acquired from patients after informed consent and ethical permission was obtained for participation in the study.
Conflict-of-interest statement: The authors have no conflict of interest to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Giuseppe Caso, MD, PhD, Department of Surgery, Stony Brook University Medical Center, 100 Nicolls Rd, Stony Brook, NY 11794, United States.
Telephone: +1-631-4441790 Fax: +1-631-4448824
Received: January 28, 2017
Peer-review started: February 7, 2017
First decision: May 8, 2017
Revised: April 28, 2017
Accepted: June 6, 2017
Article in press: June 7, 2017
Published online: August 12, 2017

To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome.


Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase (GP DH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher’s Least Significant Difference test.


Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI (14% at 48 h, P < 0.001) and PI + NRTI (19% at 48 h, P < 0.001) with additional suppression when ritonavir (RTV) was added (26% at 48 h). The drug combination of atazanavir (ATV) + RTV + emtricitabine (FTC) + tenofovir (TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity (64%) or lipid accumulation (39%), P < 0.001. Combining NRTIs with a PI (ATV + FTC + TDF) significantly suppressed differentiation (GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added (ATV + FTC + TDF + RTV, P < 0.001).


Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.

Keywords: Nucleoside reverse transcriptase inhibitors, Non-nucleoside reverse transcriptase inhibitors, Protease inhibitors, Pre-adipocytes, Highly active antiretroviral therapy, Lipodystrophy

Core tip: We demonstrated an in vitro system for evaluating potential antiretroviral regimens for adipose tissue toxicity. In general, combination regimens resulted in greater preadipocyte proliferation and differentiation inhibition than single therapies. The drug combination of atazanavir + emtricitabine + tenofovir had inhibitory effects on preadipocytes and adding ritonavir at levels equivalent to clinical boosting, increased toxicity still further.