ABSTRACT
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1-5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.
Subject(s)
Anti-Retroviral Agents/pharmacology , HTLV-I Infections/genetics , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/immunology , Immune Checkpoint Inhibitors/pharmacology , Adult , Anti-Retroviral Agents/therapeutic use , Biomarkers , Clinical Decision-Making , Cytokines , Disease Management , Drug Therapy, Combination , Female , Gene Expression Regulation/drug effects , HTLV-I Infections/drug therapy , HTLV-I Infections/virology , Host-Pathogen Interactions/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Proteins/genetics , Immune Checkpoint Proteins/metabolism , Immunologic Memory , Immunophenotyping , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Count , Male , Middle Aged , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Treatment Outcome , Viral LoadABSTRACT
Human T cell leukemia virus type 1 (HTLV-1) and Zika virus (ZIKV) have been considered neglected viruses of low public health concern until recently when incidences of HTLV-1 and ZIKV were observed to be linked to serious immune-related disease and neurological complications. This review will discuss the epidemiology, genomic evolution, virus-host interactions, virulence factors, neuropathological sequelae, and current perspectives of these reemerging viruses. There are no FDA-approved therapeutics or vaccines against these viruses, and as such, it is important for clinical trials to focus on developing vaccines that can induce cell-mediated immune response to confer long-term protective immunity. Furthermore, attention should be paid to reducing the transmission of these viruses through unprotected sex, infected blood during sharing of contaminated needles, donated blood and organs, and vertical transmission from mother to baby via breastfeeding. There is an urgent need to re-evaluate repurposing current antiviral therapies as well as developing novel antiviral agents with enhanced efficacy due to the high morbidity rate associated with these two reemerging chronic viral diseases.
