Innate immune responses represent one of the first and most potent lines of defense against infection. Importance of this surveillance network is underscored by the numerous mechanisms that pathogens have evolved to counteract and evade these responses. The success of the immediate innate immune response relies on the recognition of conserved structures, termed pathogen associated molecular patterns (PAMPs), commonly present in microbes but not in the host. Pattern recognition receptors (PRRs) act as microbial sensors for the host. The sensing of PAMPs by host PRRs initiate the induction of several intracellular signaling events, triggering the expression of cytokines and interferons, which can govern potent restrictors of pathogen infection. In this application, we propose to pursue the hypothesis that a robust innate immune recognition and response to HIV-1 exposure, likely elicited from abortive infection of myeloid cells, rises from the activation of key pattern recognition receptor (PRR) pathways and results in a localized antiviral environment that markedly decreases the likelihood of CD4+ T cell infection and subsequent spread of infection, both in the mucosa and during peripheral infection. The cGAS cytoplasmic DNA sensing pathway, which is particularly active in myeloid cells, has recently been identified as a key sensor for reverse transcribed HIV-1 DNA. Activation of this and potentially other PRR-governed pathways promote the secretion of interferons (IFNs) leading to the transcription of hundreds of interferon-stimulated genes (ISGs), some of which contribute to suppression of HIV-1 replication. Recently, we have reported the identification PQBP1 as a critical component in the recognition of early HIV-1 nucleic acid products required for activation of the cGAS DNA sensing pathway, resulting IFN induction in HIV-infected myeloid cells. Here, we propose to investigate in more detail the regulation of this novel sensing circuit, including understanding the features and accessibility of the HIV-1 PAMP, its downstream regulation, and its impact in HIV-1 transmission. A better understanding of the innate response circuitry that senses HIV-1 infection is likely to enable the development of novel therapeutic interventions against systemic HIV-1 infection, and the illumination of the molecular basis of a protective mucosal innate response to HIV-1 will be critical in next generation vaccine and adjuvant design.
This application proposes to investigate host innate immune surveillance of HIV-1 during transmission and systemic infection. Using a series biochemical and genetic tools, we will mechanistically characterize the innate immune pathway induced during HIV-1 infection and address impact of this pathway in HIV-1 transmission. A fundamental molecular understanding of this process in ex vivo, disease-relevant primary cells is a critical step in the design of animal studies to assess the contribution of this pathway in an in vivo context, facilitating the development of HIV vaccines and vaccine adjuvants.
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|Mamede, João I; Cianci, Gianguido C; Anderson, Meegan R et al. (2017) Early cytoplasmic uncoating is associated with infectivity of HIV-1. Proc Natl Acad Sci U S A 114:E7169-E7178|