- Browse by Subject
Browsing by Subject "CD8 T cell"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Disease Progression in Children With Perinatal Human Immunodeficiency Virus Correlates With Increased PD-1+ CD8 T Cells That Coexpress Multiple Immune Checkpoints(Oxford University Press, 2021) Tailor, Janki; Foldi, Julia; Generoso, Matthew; McCarty, Bret; Alankar, Aparna; Kilberg, Max; Mwamzuka, Mussa; Marshed, Fatma; Ahmed, Aabid; Liu, Mengling; Borkowsky, William; Unutmaz, Derya; Khaitan, Alka; Pediatrics, School of MedicineBackground: PD-1 marks exhausted T cells, with weak effector functions. Adults living with human immunodeficiency virus (HIV) have increased levels of PD-1+ CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1+ CD8 T cells in children with perinatal HIV. Methods: We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells; their coexpression with immune checkpoints (ICs) 2B4, CD160, and TIM3; correlates with immune activation and HIV disease progression; and HIV-specific and -nonspecific proliferative responses. Results: PD-1+ CD8 T-cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1+ CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1+2B4+CD160+TIM3- in PD-1+ CD8 T cells predicts weaker HIV-specific proliferative responses, suggesting that this subset is functionally exhausted. Conclusions: Children with perinatal HIV have high levels of PD-1+ CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1-directed immunotherapies for pediatric HIV remission and cure.Item Host Factors That Influence Coxsackievirus B3 Replication and Pathogenensis(2023-04) Dhalech, Adeeba Haroon; Robinson, Christopher M.; Hurley, Thomas D.; Katzenellenbogen, Rachel A.; Richer, Martin J.; Spinola, Stanley M.Enteric viruses are infectious human pathogens that initiate infection in the gastrointestinal tract. They follow a fecal-oral route of transmission and are spread by contamination of food, water, or contact between individuals. Furthermore, enteric viruses also cause significant morbidity, mortality, and economic burdens yearly. Coxsackievirus (CV) is commonly isolated among enteric viruses and is an etiological agent of hand, foot, and mouth disease, hemorrhagic conjunctivitis, and myocarditis. The virus predominantly infects infants and young children and accounts for 11% of the fatality rate in neonates. Despite CV’s impact on human health, there are no treatments or vaccines for CV infections. Using a mouse model to study a key CV, Coxsackievirus B3 (CVB3), our laboratory has found two critical factors that impact CVB3 replication and pathogenesis. First, we have demonstrated that intestinal bacteria enhance intestinal CVB3 replication. We found that certain specific bacteria (Salmonella enterica) and its cell wall components, like lipopolysaccharides (LPS), enhanced CVB3 stability and infectivity in vitro. Additionally, we found that particular constituents of LPS are required for stability to occur. These data suggest that specific bacteria may be integral in maintaining CVB3 infectivity in the intestine. Besides virus-microbiome interaction, CVB3 is also impacted by sex hormones. Using castrated mice models, we observed a sex bias to CVB3 infection, with male mice succumbing to CVB3-induced disease at an increased rate compared to female mice. Our data suggest that testosterone, a predominant male sex hormone, enhanced CVB3 intestinal replication and viral dissemination to organs in male and female mice, but lethality only in male mice. Moreover, testosterone also affected the immune response by reducing the activation of the CD8+ T cells. CD8+ T cells are required to clear the viral infection and are integral in vaccine development. In contrast, we found an enhanced CD8+ T cell response in female mice to CVB3 infection, suggesting a sex-dependent T cell response that may underlie the sex bias in disease. Overall, these data represent an essential advancement in the CV field and will help develop future therapeutics and aid in vaccine design to limit CV infections.