We hypothesize that several of the factors identified in Project 1 as restriction factors of HIV replication will be components of the host antiviral sensing machinery and/or of pathways downstream this sensing machinery. Restriction factors may include known and unknown stimulators of the antiviral sensing machinery leading up to the antiviral response. There are four known families of sensing molecules of viral pathogens that induce IFN and/or antiviral responses, two of them are extracytoplasmic receptors, the Tolllike receptors (TLR) and the lectin-like receptors (LLR), and the two other are cytoplasmic receptors, the Nod-like receptors (NLR) and the RlG-1-like receptors (RLR). However, very little is known about how HIV interacts with these sensing pathways and induces and/or represses an antiviral response such as the induction of IFN and/or IFN-stimulated genes (ISGs) with anti-HIV activity. We propose to determine the restriction factors that feed into these pathways and the role they play in the anti-HIV innate immune response at the cellular level. In addition, we will study the molecular regulation of these pathways during HIV infection and their impact in the HIV antiviral response. Despite the recognized antiviral activity of type I IFN, only a few specific factors that mediate the inhibitory effect of IFN on HIV replication have been identified. While in collaboration with Projects 1, 3, 4 and 6 we will generate an HIV-1 innate immune pathway activation map that includes the restriction factors identified in this PPG, we will also select 4-5 specific restrictions factors induced by IFN to study in more detail their anti-HIV-1 activities. To achieve these goals, we have assembled a team of three co-investigators with extensive experience in these innate immunity pathways who will be responsible for accomplishing the specific aims below. Dr. Garcia-Sastre has more than 12 years of experience in IFN and the RLR pathways, and their modulation during viral infection. Dr. David has been working with the interferon system for 18 years, and his lab discovered the activation of IRF-3 by virus infection and TLR ligation as a key innate immune response pathway. Dr. Reed is a leader in the area of NLR signaling. The generated data will aide in improving understanding of the interactions of HIV with innate immune systems, and will identify novel regulators of antiviral responses that may serve as future targets for developing therapeutic strategies.
Understanding the pathways leading to innate antiviral responses during HIV-1 infection will expand our knowledge of HIV replication and unravel potential new targets for therapeutic or prophylactic intervention.
|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|
Showing the most recent 10 out of 91 publications