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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-EC-A)
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Alvarez, Raymond A; Maestre, Ana M; Law, Kenneth et al. (2017) Enhanced FCGR2A and FCGR3A signaling by HIV viremic controller IgG. JCI Insight 2:e88226
Park, Ryan J; Wang, Tim; Koundakjian, Dylan et al. (2017) A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. Nat Genet 49:193-203
Ball, K Aurelia; Johnson, Jeffrey R; Lewinski, Mary K et al. (2016) Non-degradative Ubiquitination of Protein Kinases. PLoS Comput Biol 12:e1004898
Hultquist, Judd F; Schumann, Kathrin; Woo, Jonathan M et al. (2016) A Cas9 Ribonucleoprotein Platform for Functional Genetic Studies of HIV-Host Interactions in Primary Human T Cells. Cell Rep 17:1438-1452
Heaton, Nicholas S; Moshkina, Natasha; Fenouil, Romain et al. (2016) Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. Immunity 44:46-58
Guo, Haitao; König, Renate; Deng, Meng et al. (2016) NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host Microbe 19:515-528
Cheng, Zhang; Hoffmann, Alexander (2016) A stochastic spatio-temporal (SST) model to study cell-to-cell variability in HIV-1 infection. J Theor Biol 395:87-96
Ramage, Holly R; Kumar, G Renuka; Verschueren, Erik et al. (2015) A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol Cell 57:329-340
Ayllon, Juan; García-Sastre, Adolfo (2015) The NS1 protein: a multitasking virulence factor. Curr Top Microbiol Immunol 386:73-107
Shah, Priya S; Wojcechowskyj, Jason A; Eckhardt, Manon et al. (2015) Comparative mapping of host-pathogen protein-protein interactions. Curr Opin Microbiol 27:62-8

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