TGF-Mediated Downregulation of Thrombopoietin Is Associated With Platelet Decline in Asymptomatic SIV Infection

Metcalf Pate, Kelly A. DVM, PhD*; Lyons, Claire E. BS*; Dorsey, Jamie L. BS*; Queen, Suzanne E. MS*; Adams, Robert J. DVM*; Morrell, Craig N. DVM, PhD; Mankowski, Joseph L. DVM, PhD*,‡,§

JAIDS Journal of Acquired Immune Deficiency Syndromes: 15 April 2014 - Volume 65 - Issue 5 - p 510–516
doi: 10.1097/QAI.0000000000000048
Basic and Translational Science

Background: Thrombocytopenia is a known consequence of HIV infection, and decreased production of platelets has been previously implicated in the pathogenesis of platelet decline during asymptomatic infection. Thrombopoietin (THPO) drives platelet production by stimulating the maturation of bone marrow megakaryocytes and can be transcriptionally downregulated by cytokines that are increased during infection such as transforming growth factor β (TGFβ) and platelet factor 4 (pf4).

Design: To determine whether transcriptional downregulation of THPO contributed to decreased platelet production during asymptomatic infection in the simian immunodeficiency virus (SIV)/macaque model of HIV, we compared hepatic THPO mRNA levels to platelet number and megakaryocyte density. To identify potential inhibitory factors that decrease THPO transcription during asymptomatic infection, we measured TGFβ and pf4 plasma levels. To determine whether combined antiretroviral therapy (cART) could correct platelet decline by altering cytokine levels, we measured TGFβ and pf4 in cART-treated SIV-infected macaques and compared these values to cART-untreated SIV-infected macaques.

Results: Hepatic THPO transcription was downregulated during asymptomatic SIV infection concurrent with platelet decline. Hepatic THPO mRNA levels correlated with bone marrow megakaryocyte density. In contrast, plasma TGFβ levels were inversely correlated with hepatic THPO transcription and bone marrow megakaryocyte density. With cART treatment, plasma TGFβ levels and platelet count returned to values similar to those in uninfected macaques.

Conclusions: TGFβ-mediated downregulation of hepatic THPO may lead to decline in platelet number during asymptomatic SIV infection, and cART may prevent platelet decline by normalizing plasma TGFβ levels.

*Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD;

Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY;

Department of Pathology; and

§Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.

Correspondence to: Joseph L. Mankowski, DVM, PhD, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 N. Broadway, MRB 827, Baltimore, MD 21205-2196 (e-mail: jmankows@jhmi.edu).

K.A.M.P. and J.L.M. supported by the National Institutes of Health (NIH) (R25 MH080661). K.A.M.P. was also supported by the NIH (T32 OD011089). J.L.M. received NIH grant (R01 HL078479) and was supported by the National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) and the NIH (P40 OD013117).

Some of these data were presented as a poster by K.A.M.P. at the Platelets 2012 International Symposium, June 7–11, 2012, Beverly, MA.

The remaining authors have no conflicts of interest to disclose.

Received October 25, 2013

Accepted October 25, 2013

© 2014 by Lippincott Williams & Wilkins