Retroviral b‐Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity immune checkpoint (ICP) molecules such as PD-1 PD-L1/PD-L2, negatively associates with cytolytic potential T cells in individuals HAM/TSP. Interestingly, ICPs can exist soluble cell-free form be carried on extracellular vesicles (EVs) exosomes (small EVs, <300 nm) while maintaining their immunomodulatory activity. Therefore, we investigated role exosomal HTLV-1 associated neuroinflammation. For very first time, demonstrate unique elevated presence several stimulatory (CD27, CD28, 4-1BB) inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors HAM/TSP sera, purified from HAM/TSP-derived HTLV-1-producing (OSP2) cells. These were found to co-localized endosomal sorting complex required for transport (ESCRT) pathway proteins exhibited functional binding respective ligands. Viral cytokines (primarily IFNγ) present exosomes. IFNγ exposure enhanced release antiretroviral drugs (Azidothymidine Lopinavir) significantly inhibited this process. b-Zip protein (HBZ) has been linked factors enhance EV concurrent knockdown here led reduced ESCRT genes (e.g., Hrs, Vsp4, Alix, Tsg101) well abrogated molecules, suggesting HBZ involvement Moreso, OSP2 adversely affected CD8 T-cell functions by diminishing levels cytotoxic factors. Collectively, these findings highlight exosome-mediated immunomodulation pathways an underlying mechanism context HTLV-1-induced