Investigation of cellular mechanism of PQBP1-dependant innate signaling of HIV-1

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In a collaborative publication, we identified PQBP1 as an essential component of the cGAS/IRF3-dependent innate response to HIV. We could demonstrate that PQBP1 binds directly to HIV-1 reverse-transcribed DNA intermediates, and binds to cGAS to induce STING/IRF3 signaling. Interestingly, the requirement for PQBP1 appears to be specific for lentiviral DNA, as other types of DNA, including poxvirus, did not require PQBP1 to stimulate innate immune responses. The main goals of this project are to define the specificity of PQBP1-dependent sensing and the underlying mechanisms. Initially, we will examine other genera of the Retroviridae family in comparison to DNA viruses to understand the breadth of PQBP1 recognition. Moreover, we aim to detect the reverse transcribed DNA intermediates bound to PQBP1 in order to understand their commonalities. Furthermore, we aim to analyze whether cGAS is required for this step. Furthermore, we are interested in the underlying mechanisms. We will determine whether infection of viruses recognized by PQBP1 specifically enhance the binding between PQBP1 and cGAS and whether specific PTMs are involved. Our results will provide new insights into the cellular mechanism underlying PQBP1-dependant innate signaling of HIV-1.