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

Abstract

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

Machine learning models based on fluid immunoproteins that predict non-AIDS adverse events in people with HIV

“… 44 , 45 However, soluble immune checkpoints have also been shown to be associated with disease outcomes in other viral infections, including human T-lymphotropic virus type 1 (HTLV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 46 , 47 , 48 While these biomarkers are not restricted to HIV, they could allude to immune perturbations that would lead to morbidity development. Furthermore, it would be optimal to determine whether the panel of biomarkers we evaluated paired with our ML approach can assess morbidity events that occur in other viral infections, or rather our findings are specific to HIV.…”

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy

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Antibody and Cell-Based Therapies against Virus-Induced Cancers in the Context of HIV/AIDS

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