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

Abstract

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 down-regulated by cytokines that are increased during infection such as TGFβ and pf4. Design To determine whether transcriptional down-regulation of THPO contributed to decreased platelet production during asymptomatic infection in the 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 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 untreated SIV-infected macaques. Results Hepatic THPO transcription was down-regulated 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.

Platelets and Infection – An Emerging Role of Platelets in Viral Infection

“…They are able to influence the cytokine profile of the host, resulting in altered TPO production in the liver. Examples of this include: simian immunodeficiency virus (SIV), which triggers TPO production via up-regulation of tumor growth factor (TGF) β ( 17 ); human herpes virus 6, which can interfere with TPO-inducible megakaryocytic colony formation ( 18 ); human herpes virus 7, which impairs the survival and differentiation of megakaryocytes ( 19 ).…”

Paving the path to HIV neurotherapy: Predicting SIV CNS disease

“…These data are consistent with previously published studies by our group (Wachtman 2006 & Metcalf Pate 2013) and emphasize the importance of considering absolute change from baseline platelet count as a prognostic indicator of increased risk for the development of HIV-associated CNS disease. This predictive platelet loss represents the combined effect of decreased platelet production (Metcalf Pate 2014), increased platelet destruction (Metcalf Pate 2013), and increased activated platelet associations with monocytes and endothelium (Metcalf Pate unpublished data), and may reflect the fundamental role of platelets in the pathogenesis of lentivirus-associated CNS disease.…”

Elevated thrombopoietin and platelet indices confirm active thrombopoiesis but fail to predict clinical severity of puumala hantavirus infection

“…[16] In a macaque model of HIV, transforming growth factor b (TGFb) downregulates TPO, and combined antiretroviral therapy corrects both plasma TGFb level and platelet count. [17] In severe acute respiratory syndrome induced by a novel coronavirus, TGFb inhibits the effect of high TPO on megakaryocytopoiesis. [18] Inflammatory mediator interleukin 6 (IL-6), however, increases TPO production both in vitro and in vivo.…”