The innate immune response alerts the host to infection before an adaptive immune response has a chance to develop. Viral nucleic acids introduced into cells or synthesized during infection trigger cytosolic sensors of innate immunity to produce antiviral cytokines, such as type I interferons (IFN). Some viruses evade immune sensing. The increase in viremia during acute stages of infection are associated with widespread activation of DCs and activation of IFN, although HIV infection of target cells such as T cells and macrophages does not induce intrinsic antiviral IFN responses. This application focuses on intracellular innate immunity in target cells and aims to understand how HIV avoids innate immune activation. Prior to work conducted by the Principal Investigator (PI), intracellular innate immune recognition of retroviruses especially HIV has been a key information gap in our existing knowledge regarding innate immune recognition of viruses. We recently discovered that the cytosolic exonuclease TREX1 suppressed the IFN response triggered by HIV DNA. In Trex1-/- mouse cells and human CD4+ T cells and macrophages in which TREX1 was inhibited by RNAi, HIV DNA accumulated in the cytosol and HIV infection induced IFN production that inhibited HIV replication and spreading. Our study suggested that cytosolic HIV DNA is a key pathogen-associated molecular pattern (PAMP) that can be detected by innate immunity and activate IFN and pro-inflammatory cytokine production, and that HIV exploits host factors (such as TREX1) to subvert innate immune detection. We also provide extensive preliminary data that uncover a cytosolic DNA detection pathway involved in the recognition of HIV DNA, and a novel mechanism by which TREX1 inhibits IFN induction.
The specific aims of this proposal are 1) To define the role(s) of an innate immune DNA sensing pathway in the recognition of cytosolic HIV DNA. 2) To characterize how TREX1 inhibits the innate immune response to HIV. 3) To characterize how the opposing dynamic between HIV innate immune detection and HIV innate immune evasion contributes to the establishment of infection by HIV. Our proposed study will elucidate the molecular mechanisms of how HIV subvert innate immune responses, and lay the foundation for harnessing intracellular innate immunity as a novel avenue of therapeutics.

Public Health Relevance

Despite significant progress in HIV research, it remains elusive why the host immune response is unable to control viral replication in most infected individuals. By elucidating the molecular mechanisms of how HIV subverts innate immune responses in target cells, it may be possible to develop new therapeutic approaches to enhance innate immunity during the critical early stages of HIV transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098569-03
Application #
8610237
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Stansell, Elizabeth H
Project Start
2012-02-03
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Kucej, Martin; Fermaintt, Charles S; Yang, Kun et al. (2017) Mitotic Phosphorylation of TREX1 C Terminus Disrupts TREX1 Regulation of the Oligosaccharyltransferase Complex. Cell Rep 18:2600-2607
Gonugunta, Vijay K; Sakai, Tomomi; Pokatayev, Vladislav et al. (2017) Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response. Cell Rep 21:3234-3242
Aroh, Chukwuemika; Wang, Zhaohui; Dobbs, Nicole et al. (2017) Innate Immune Activation by cGMP-AMP Nanoparticles Leads to Potent and Long-Acting Antiretroviral Response against HIV-1. J Immunol 199:3840-3848
Pokatayev, Vladislav; Yan, Nan (2017) Methods of Assessing STING Activation and Trafficking. Methods Mol Biol 1656:167-174
Hasan, Maroof; Gonugunta, Vijay K; Dobbs, Nicole et al. (2017) Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism. Proc Natl Acad Sci U S A 114:746-751
Hasan, Maroof; Yan, Nan (2016) Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacol Res 111:336-342
Starokadomskyy, Petro; Gemelli, Terry; Rios, Jonathan J et al. (2016) DNA polymerase-? regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol 17:495-504
Pokatayev, Vladislav; Hasin, Naushaba; Chon, Hyongi et al. (2016) RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J Exp Med 213:329-36
Hasan, Maroof; Dobbs, Nicole; Khan, Shaheen et al. (2015) Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice. J Immunol 195:4573-7

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