TGFβ-Mediated Downregulation of Thrombopoietin Is Associated With Platelet Decline in Asymptomatic SIV Infection.
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).


METHODS
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.
Kelly A
KA
Metcalf Pate
Claire E
CE
Lyons
Jamie L
JL
Dorsey
Suzanne E
SE
Queen
Robert J
RJ
Adams
Craig N
CN
Morrell
Joseph L
JL
Mankowski
D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D058070:Asymptomatic Diseases; D015536:Down-Regulation; D020869:Gene Expression Profiling; D008099:Liver / Q000473:pathology; D008254:Macaca nemestrina; D008297:Male; D008533:Megakaryocytes / Q000502:physiology; D010976:Platelet Count; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology*; D013921:Thrombocytopenia; D034061:Thrombopoiesis; D013926:Thrombopoietin / Q000096:biosynthesis* / Q000097:blood; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016896:Treatment Outcome
D044966:Anti-Retroviral Agents; D016212:Transforming Growth Factor beta; D013926:Thrombopoietin