SAMHD1 activity underlies Ifn responses and sex-dependent differences in macrophage infection by HIV-1

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Title SAMHD1 activity underlies Ifn responses and sex-dependent differences in macrophage infection by HIV-1
Publication Type dissertation
School or College School of Medicine
Department Pathology
Author Matthew Alan Szaniawski
Date 2018
Description Human Immunodeficiency Virus type 1 (HIV-1) targets immune cells, including CD4+ T cells, macrophages, and dendritic cells (DC). Macrophages are critically important for their contributions to viral propagation and inflammation in vivo during infection, though the current understanding of host-pathogen interactions in this cell type remains deeply inadequate. A better understanding of how HIV-1 infects macrophages despite facing numerous cellular defenses may inform therapeutic approaches aimed at preventing HIV-1 infection and its sequelae. A major component of the anti-HIV-1 defense is SAM domain and HD domain-containing protein 1 (SAMHD1), a phosphohydrolase responsible for restricting the generation of double-stranded viral DNA (dsDNA) from a single-stranded RNA (ssRNA) genome. It functions by converting deoxynucleoside triphosphates (dNTP) to deoxynucleosides (dN) in non-cycling cells, a process dependent on tetramerization that is inhibited through threonine-592 (T592) phoshphorylation. We discovered that SAMHD1 activity is a critical determinant of HIV-1 infection in macrophages, and that despite its abundant expression, can exist in an inactive state (phosphor-T592) allowing macrophages to be highly susceptible to HIV-1. We found that biological sex is a major determinant of macrophage infectivity with HIV- 1, and that the relative susceptibility of male- versus female-derived macrophages hinges exclusively on SAMHD1 activity. Furthermore, we have established SAMHD1 as the principal effector through which diverse interferons (IFN) act in macrophages, and that activation of SAMHD1 through IFN signaling establishes a state of HIV-1 resistance. We find that cyclin-dependent kinase 1 (CDK1) is the major determinant of IFN-induced SAMHD1 activation, and that depletion of CDK1 through siRNA alone drives SAMHD1 activation in MDM. Interestingly, a variety of FDA-approved tyrosine kinase inhibitors (TKI) phenocopy the effects of IFNs, and their activity depends on their ability to activate SAMHD1. Furthermore, we find that macrophage infection with HIV-1 induces a similar state of protection from subsequent challenge, which correlates with activation of SAMHD1. Interestingly, this protection does not appear to involve the production of IFNs. Using phosphoproteomic and RNA-sequencing approaches, we have begun to unravel the pathways responsible for SAMHD1 activation resulting from HIV-1 sensing, IFN stimulation, and the use of TKIs, which exhibit overlapping but distinct mechanisms of action.
Type Text
Publisher University of Utah
Subject Microbiology; Immunology; Virology
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Matthew Alan Szaniawski
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s68d4s8r
Setname ir_etd
ID 1486760
Reference URL https://collections.lib.utah.edu/ark:/87278/s68d4s8r
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