The advent of antiretroviral therapy (ART) has drastically changed the epidemiology of Acquired Immunodeficiency Syndrome (AIDS). Indeed, human immunodeficiency virus (HIV) patients treated with ART can expect to live for decades and chronic diseases, such as atherothrombosis, are replacing acute infections as important causes of morbidity and death. In the current proposal we unexpectedly demonstrate that megakaryocytes and platelets express endogenous reverse transcriptase (RT) activity, which is specifically blocked by nucleoside analog RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). We also show that inhibition of platelet RT activity leads to the loss of translational repression and the formation of "stress" platelets, which are hyperactive and prone to cause thrombosis. Our robust preliminary data will be leveraged to test the overall hypothesis that ART induces platelet malfunction by directly inhibiting endogenous RT activity in megakaryocytes and platelets, which contributes to the development of atherothrombosis in HIV patients.
These aims will be executed by a research team with expertise in platelet biology, virology, thrombosis, and HIV that includes two early stage investigators with outstanding track records. Moreover, this team includes both basic scientists and clinician scientists, providing a strong, multidisciplinary group of investigators that has the experience and training to successfully complete these investigations. Questions proposed by our multi-investigator team are innovative because they explore a novel activity of megakaryocytes and platelets, reverse transcriptase, that may have previously-unrecognized functional consequences in health and disease. They also have immediate clinical significance because new information will be generated regarding the off-target effects of ART that contribute to HIV-related atherothrombosis. Dissecting the mechanisms by which ART regulates reverse transcriptase activity in megakaryocytes and platelets will shed light on how this molecular pathway operates and functions in eukaryotic cells and, in parallel, provide insight into how ART contributes to atherothrombotic events in patients with HIV.

Public Health Relevance

Our proposed research will investigate basic mechanisms underlying HIV-associated atherothrombosis and is responsive to the goals of this RFA (RFA-HL-14-024). We will determine whether inhibition of endogenous reverse transcriptase (RT) activity releases translational suppression in human platelets and precursor megakaryocytes, inducing a hyperreactive, stress platelet phenotype. Dissecting the mechanisms by which antiretroviral therapy (ART) regulates RT activity in platelets will provide insight into how ART contributes to atherothrombotic events in patients with HIV.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL126547-01
Application #
8847014
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Kindzelski, Andrei L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Machlus, Kellie R; Wu, Stephen K; Stumpo, Deborah J et al. (2016) Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation. Blood 127:1468-80
Yost, Christian C; Schwertz, Hansjörg; Cody, Mark J et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest 126:3783-3798
Koliopoulou, Antigone; McKellar, Stephen H; Rondina, Matthew et al. (2016) Bleeding and thrombosis in chronic ventricular assist device therapy: focus on platelets. Curr Opin Cardiol 31:299-307
Shih, Lauren; Kaplan, David; Kraiss, Larry W et al. (2016) Platelet-Monocyte Aggregates and C-Reactive Protein are Associated with VTE in Older Surgical Patients. Sci Rep 6:27478
Rowley, Jesse W; Chappaz, Stéphane; Corduan, Aurélie et al. (2016) Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. Blood 127:1743-51
Planelles, Vicente (2015) An Ounce of Tat Prevention Is Worth a Pound of Functional Cure. MBio 6:
Rondina, M T; Weyrich, A S (2015) Regulation of the genetic code in megakaryocytes and platelets. J Thromb Haemost 13 Suppl 1:S26-32
Franks, Zechariah; Carlisle, McKenzie; Rondina, Matthew T (2015) Current challenges in understanding immune cell functions during septic syndromes. BMC Immunol 16:11
Pache, Lars; Dutra, Miriam S; Spivak, Adam M et al. (2015) BIRC2/cIAP1 Is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency. Cell Host Microbe 18:345-53
Kaplan, David; Casper, T Charles; Elliott, C Gregory et al. (2015) VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. Chest 148:1224-30

Showing the most recent 10 out of 16 publications