Inflammation and CMV-associated lymphocyte senescence in chronic HIV infection

Heath, John J. (2018) Inflammation and CMV-associated lymphocyte senescence in chronic HIV infection. Masters thesis, Memorial University of Newfoundland.

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Abstract

While acute inflammation is important in immune responses to infection, chronic systemic inflammation intrinsically underlies age-associated pathologies. Lifelong cellular turnover equates biological age with long term accumulation of senescent cells, characterized by cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP). Currently, the exact contributions of lymphocytes to the inflammatory landscape seen during aging remains understudied. Cytomegalovirus (CMV) infection creates an inflated, potentially senescent, CD8⁺ T lymphocyte population, often exaggerated in age and in particular, human immunodeficiency virus (HIV) infection. Many living with long-term HIV infection often suffer “premature” age-related illnesses. Frequent rounds of antigen-driven expansion of CMV-specific lymphocytes could introduce a telomere-dependent SASP and a role in suspected age-related pathology. Using a 4-parameter flowFISH assay to quantify telomere length in peripheral blood lymphocytes, we show in HIV-infected CMV-seropositive individuals (n=32) that CD57⁺CD8⁺ T cells responding to CMV had the shortest telomere lengths compared to CD57⁺CD8⁺, global CD8⁺ and CD8⁺ T cells responding to HIV (p < 0.001, 0.001, 0.04, respectively). CMV-seropositive HIV-infected study groups (n=97) show higher circulating pro-inflammatory cytokine levels than those not infected with CMV (n=19), further linking CMV immunity, immune senescence and inflammation. Our data support consideration that CMV infection associated expansion of CD8⁺ T cells compound the effects of natural aging on chronic inflammation.

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