Innate immune defense sensors and signaling pathways represent the first line of defense against infection by microbial pathogens, including HIV, the causative agent of AIDS. The goals of this specific project are to help define the immune defense pathways that regulate specific stages ofthe HIV-1 replication cycle, and to contribute to the development of kinetic mathematical models that can explain, and predict, the early innate immune response to HIV-1 infection. The early steps of virus replication that will be analyzed are those leading up to virus-cell membrane fusion, reverse transcription, nuclear import, and viral DNA integration. The late steps that will be analyzed are viral gene expression, RNA splicing, translation, and virus assembly/release. These studies exploit a unique dataset that includes candidate innate immune factors that were identified either through genome-wide siRNA or cDNA screening for their effects on HIV-1 infection. There is substantial overiap between these candidate genes and those in the innate immune database, interferon-stimulated genes, and genes under positive selection. However, approximately 15% of the candidate genes have not been implicated before in innate immune responses and these are potentially new players in the innate response to HIV-1. Our studies will also evaluate the roles of HIV-1 accessory proteins Vif, Vpr, Nef, and Vpu, as candidate viral countermeasures of specific innate immune factor functions. Taken together, these studies will significantly advance the understanding of the innate immune response to HIV-1 infection at a systems-wide level and they will contribute to the development of mathematical models that can predict the nature of these innate responses, providing valuable new insights into antiviral and vaccine approaches.

Public Health Relevance

We are attempting to understand the comprehensive innate immune response to early HIV-1 infection using a systems biology approach. Candidate innate immune factors, that we have identified, will be tested for their effects on the rates of different steps of HIV-1 replication. This information will be used to generate mathematical models that can explain and predict the behavior of these responses, information that will be invaluable for future antiviral and vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI090935-04
Application #
8516994
Study Section
Special Emphasis Panel (ZAI1-EC-A)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$435,615
Indirect Cost
$28,318
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60
Dahabieh, Matthew S; Ooms, Marcel; Brumme, Chanson et al. (2014) Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NF?B. Retrovirology 11:17
Shi, Mude; Cho, Hyelim; Inn, Kyung-Soo et al. (2014) Negative regulation of NF-?B activity by brain-specific TRIpartite Motif protein 9. Nat Commun 5:4820
Manganaro, Lara; Pache, Lars; Herrmann, Tobias et al. (2014) Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-?B-dependent manner. J Virol 88:7528-40
Opaluch, Amanda M; Schneider, Monika; Chiang, Chih-yuan et al. (2014) Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-?. PLoS One 9:e89284
Morris, John H; Knudsen, Giselle M; Verschueren, Erik et al. (2014) Affinity purification-mass spectrometry and network analysis to understand protein-protein interactions. Nat Protoc 9:2539-54
Emig-Agius, Dorothea; Olivieri, Kevin; Pache, Lars et al. (2014) An integrated map of HIV-human protein complexes that facilitate viral infection. PLoS One 9:e96687
Rajsbaum, Ricardo; Versteeg, Gijs A; Schmid, Sonja et al. (2014) Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKK? kinase-mediated antiviral response. Immunity 40:880-95
Lu, Huasong; Li, Zichong; Xue, Yuhua et al. (2014) AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc Natl Acad Sci U S A 111:E15-24
Monroe, Kathryn M; Yang, Zhiyuan; Johnson, Jeffrey R et al. (2014) IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428-32

Showing the most recent 10 out of 36 publications