Heterosexual transmission is the dominant mode of HIV-1 acquisition woridwide. Understanding the eariy innate immune response in the mucosa is, thus, essential for devising novel strategies to prevent infection. Compelling evidence suggests that immunological events occurring during the first days and weeks after HIV-1 infection are critical determinants shaping the course of HIV-1/AIDS disease. The mechanisms that underiie the failure of innate immune responses to restrict HIV-1 infection are currently under intense investigation. The goal of this program project is to dissect the early events in the innate immune response directed at HlV-1 using a systems biology approach. Our proposal (project 4) will use a primary DC-T cell system to test the hypothesis that HIV-1 manipulates the kinetics of human innate immune responses by interfering with dendritic cell (DC) function, in particular, the induction of type I interferon (IFN) in those cells. We speculate that HIV-1 delays DC maturation and that one or more of the HIV-1 proteins encodes an IFN antagonist.
In specific aim #1 we will determine the reciprocal impact of HIV-1 infection and IFN/pattern recognition response signaling on each other.
In specific aim #2 we will evaluate the role of newly identified cellular restriction factors in DCs within the context of viral infection. We will assess the efficiency of viral replication and transfer from dendritic cells to T lymphocytes, the pattern of DC activation and the IFN/PRR signaling pathways. We will use lentiviral transduction systems to down-regulate or over-express selected host factors (50-100) to test the effect of their gain or loss of function in myeloid DC lineages and T lymphocytes.
In specific aim #3 we will identify putative viral inhibitors of DC maturation and IFN production using a series of primary viral isolates of different subtypes, HIV-1 full-length molecular clones deleted of accessory genes. We will confirm and expand our findings by inserting single accessory and regulatory HIV-1 genes into recombinant Newcastle Disease Virus (NDV) vectors which induce rapid and strong innate immune responses. This project combines the complementary areas of expertise of Dr. Ana Fernandez- Sesma and Dr. Viviana Simon. Dr. Fernandez-Sesma has extensive experience with primary human DCs and the initiation of immune responses in those cells by different viruses, such as Influenza, Dengue (DENV) and NDV. Dr. Simon has great expertise in HIV-1 molecular virology and host factors influencing HlV-1 replication, such as AP0BEC3. The results of our project will serve as raw data forthe mathematical models generated in project 6. This research project will determine the role of the restriction factors identified in project 1 and 2 on signaling, DC maturation, innate immune responses and viral inhibition in DCs and Tlymphocytes, both primary cell populations most relevant to mucosal immunity.
Collectively, information generated in this proposal will help understand how changes in the virus influence immunogenicity in humans. This knowledge will be critical for a) defining the correlate of immunity and protection in HIV infection and b) developing more efficient HIV vaccines
|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