Human immunodeficiency virus (HIV) infection of host cells initiates innate immune signaling pathways that result in the expression of type I interferons and pro?inflammatory cytokines that interfere with the life cycle of the virus. The virus can bring about measures that not only allow it to escape detection within the cell, but also to use the components of the immune signaling pathways for its own advantage. Studies of mechanisms by which HIV evades the antiviral innate immune responses provide the scientific impetus to characterize the genetic polymorphisms that can affect components of the host signaling pathways. We will conduct a cohort study to determine whether the host proteins identified by genome?wide functional screens for which a plausible biological mechanism of action for the gene is found contributes to HIV/AIDS susceptibility. We will look at the association between genetic variants (both known and previously unknown) and HIV/AIDS susceptibility using biological samples and information obtained from men enrolled in the Multicenter AIDS Cohort Study (MACS). This will allow us to undertake detailed studies of sufficient sample size to distinguish the proposed effect of a factor of functional relevance from no effect convincingly. Our objective is to undertake a "holistic" approach to the systematic examination of how the virus and antiviral innate immune responses intersect to discover how the patterns of genetic variation and differences in gene expression of the factors that are involved in signaling pathways may contribute to HIV disease. The rationale for our approach is that each of the described host?related factors are relevant to only a small proportion of people who continue to resist HIV/AIDS. Defining how HIV subverts the innate immune response is thus important for systems?level understanding of the innate immune response and rational design of improved therapies.
Our specific aims are to: distinguish polymorphisms most likely to affect function ofthe systematically identified network of genes underlying the innate immune response to HIV infection;and examine the association between genetic polymorphism in the candidate innate immune response genes and HIV/AIDS susceptibility. Through collaboration with the other Projects, we will collect a comprehensive quantitative data set to attain systems?level understanding of antiviral innate immune responses.
When applied to HIV/AIDS, a systems biology model will predict the response of cellular mechanisms that are used to detect and defend against the virus. The identification of mutations that influence the activity of a protein may help to define new therapies. Thus, the proposed research can positively impact public health by contributing to the understanding and treatment of HIV/AIDS.
|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|
|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|
|Guo, Haitao; KÃ¶nig, 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 19:515-28|
|Blakely, Collin M; Pazarentzos, Evangelos; Olivas, Victor et al. (2015) NF-ÎºB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep 11:98-110|
|Sherrill-Mix, Scott; Ocwieja, Karen E; Bushman, Frederic D (2015) Gene activity in primary T cells infected with HIV89.6: intron retention and induction of genomic repeats. Retrovirology 12:79|
|Zhang, Xianqin; Bogunovic, Dusan; Payelle-Brogard, BÃ©atrice et al. (2015) Human intracellular ISG15 prevents interferon-Î±/Î² over-amplification and auto-inflammation. Nature 517:89-93|
|Costa, Helio A; Leitner, Michael G; Sos, Martin L et al. (2015) Discovery and functional characterization of a neomorphic PTEN mutation. Proc Natl Acad Sci U S A 112:13976-81|
|Manganaro, Lara; de Castro, Elisa; Maestre, Ana M et al. (2015) HIV Vpu Interferes with NF-ÎºB Activity but Not with Interferon Regulatory Factor 3. J Virol 89:9781-90|
|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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