Consequences of CTL-mediated immune pressure for HIV-1 capsid stability and innate sensing

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It is well established that HIV-1 can evade virus-specific cellular immune responses by selecting for sequence variations within targeted regions. Cellular immune responses in individuals encoding for protective HLA class I alleles, including HLA B27 and B57, preferentially target epitopes within conserved regions of p24 Gag capsid. Despite frequent viral escape from cellular immune responses, control of viral replication is maintained in these individuals. Here we propose to test the novel hypothesis that immune-driven escape mutations within HIV-1 capsid modulate capsid stability and enhance innate immune sensing of viral oligonucleotides by cytoplasmatic receptors. This hypothesis is based on the results of strong published and preliminary data demonstrating the feasibility of the proposed studies, and will be tested in two research objectives: (1) to determine the impact of CTL-driven viral escape mutations within HIV-1 capsids on capsid stability; (2) to assess the consequences of immune-modulated capsid stability for sensing of viral oligonucleotides by cytoplasmatic receptors. The proposed project is well integrated within the DFG Priority Programme Innate Sensing and Restriction of Retroviruses (SPP 1923), and will tremendously benefit from the collective expertise assembled within the Programme. These studies will bridge an important gap in our knowledge by linking viral escape within capsid from cellular immune pressure to enhanced innate sensing of viral escape variants and viral control through host restriction factors.