Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control

项目总结

PROJECT SUMMARY This project will explore strategies to target epigenetic pathways for achieving sustained HIV remission and treatment of HIV associated-central nervous system (CNS) dysfunction. The conjugation of small ubiquitin- SUMO proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for various downstream activities. SUMO proteins are also important in anti-viral immunity, opposing viral replication and mediating interferon-dependent anti-viral mechanisms. Thus, pathogens have evolved to exploit the host SUMOylation machinery to ensure viral persistence and pathogenesis. During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates the host SUMOylation machinery to ensure its viral replication in CD4+ manipulates Microglia T cells, however, whether HIV-1 the SUMO paralogs to control its replication and/or atency in glial cells like microglia is unclear. are the main HIV-1 target cells in the CNS and constitute an important reservoir for viral pathogenesis. l In microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multi-enzymatic chromatin- modifying complex and establishes a heterochromatic environment at the HIV-1 promoter, leading to HIV-1 silencing. Studies have shown that post-translational modifications (PTMs), including phosphorylation and SUMOylation, mediate CTIP2's interactions with other proteins and complexes. Similarly, tripartite motif- containing protein 28 (TRIM28), a known SUMO E3 ligase, associates with CTIP2 in the heterochromatin complex to inhibit HIV-1 viral replication. While regulating respectively, unknown. productive SUMOylation inducible SUMOylation and phosphorylation have been implicated in the activity of CTIP2 and TRIM28 in the context of T-cell signaling events and immune responses, the impact of PTMs in the initiation and establishment of HIV-1 latency in microglia remains To this end, this proposal's central hypothesis is that the host SUMOylation system is i mpaired during HIV-1 infection in microglia and that latency is established as a result of the estoration of of host proteins. To test this hypothesis , we will use immortalized human microglial cell lines and pluripotent stem cells (iPSCs), including a novel model of HIV-1 latency. r We will also identify the SUMO-modified proteome of human microglial cells during human HIV-1 infection.