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A.A.A., S.M., and K.M.E. elderly persons, CMV-specific T cells can comprise up to 40% of CD8+ T cells,5,6 have shortened telomeres, have little to no proliferative capacity to new antigens, and are resistant to apoptosis.7 CMV seropositivity and high proportions of terminally differentiated CMV-specific T cells characterize an immune risk profile that is associated with increased mortality risk among elderly populations.8 An association between an increased proportion of CMV-specific CD4+ T cells or CMV IgG and neurofibrillary tangles in Alzheimer’s disease provides evidence of a relationship between immune responses to CMV BOP sodium salt and cognitive changes.9 Among HIV-uninfected elderly populations, CMV-specific IgG levels are also associated with institutionalization,7 poor functional status,1,10 frailty,2,11,12 and mortality.12C15 Whether CMV directly contributes to complications BOP sodium salt of aging or whether CMV leads to immune senescence, or immune activation and inflammation, which subsequently lead to physical function impairment and frailty, is unclear. Prior studies have exhibited associations between CMV IgG and mortality, and CMV IgG and interleukin (IL)-6 and tumor necrosis factor (TNF)-12,14 suggesting that chronic CMV infection contributes to age-related Rabbit Polyclonal to Ku80 complications through heightened inflammation. Both CMV IgG and the percentage of CMV-specific T cells are higher in persons with HIV contamination compared to HIV-uninfected controls,3,16 and CMV-specific T cells are higher among HIV-infected persons on antiretroviral therapy (ART) compared to ART-naive persons.3,17 CMV-specific cell-mediated immune responses increase with age such that the highest percentages of CMV-specific CD4+ or CD8+ T cells are seen among HIV-infected older adults on ART.18 These CMV-specific humoral and cell-mediated immune responses are associated with comorbid disease markers among virologically suppressed HIV-infected persons.19C21 Furthermore, reductions in immune activation, as measured by the percentage of CD38+HLA-DR+CD8+ T cells, among HIV-infected, CMV-seropositive participants after treatment with valganciclovir, an inhibitor of CMV replication, provide direct evidence that CMV drives immune activation during chronic HIV infection.22 We have previously demonstrated a strong association between markers of inflammation and immune activation with physical function impairment BOP sodium salt among middle-aged HIV-infected persons on effective ART.23 The BOP sodium salt goals of the present study were to (1) determine the relationship between CMV-specific humoral and cell-mediated immune responses and functional impairment in well-controlled HIV infection and (2) explore the impact of clinical characteristics, inflammation, and immune activation on those relationships. Materials and Methods Study population Details of the study population, clinical assessments, and measurement of markers of inflammation, immune activation, and immune senescence have been previously published.23C25 Briefly, individuals with HIV-1 infection on antiretroviral therapy for a minimum of 6 months and no plasma HIV-1 RNA >200 copies/ml within the prior 6 months underwent physical function testing by the Short Physical Performance Battery and Fried’s frailty assessment. Cases with low physical function, defined by a combination of deficits on both functional assessments,23 were matched by age, gender, and time since HIV diagnosis to controls with high physical function (no deficits on either functional assessment). Stored samples and existing data were used for the current study. Veterans Aging Cohort Study (VACS) Index scores were calculated as previously described.26 Approval was obtained by the Colorado Multiple Institutional Review Board and informed consent was obtained from all participants. Quantitative immunoglobulins Plasma IgG antibodies against CMV, varicella zoster virus (VZV), and combined herpes simplex virus (HSV) 1 and 2 were measured in stored specimens using enzyme immunoassay kits (Diamedix Corp., Miami, FL). All assays were performed according to the manufacturer’s instructions, with the following exception: the VZV IgG kit was modified to include a standard curve consisting of the World Health Organization Biological Standard #90/690 (National Institute for Biological Standards and Control, NIBSC, Hertfordshire, UK) diluted from 20 milli-international units per milliliter (mIU) to 0.625?mIU/ml. CMV-specific T cell responses Cryopreserved peripheral blood mononuclear cells (PBMCs) were thawed and resuspended in RPMI 1640 plus 10% human Ab serum with the addition of anti-CD28 and -CD49d monoclonal antibodies (mAbs) (1?g/ml; BD Biosciences, San Jose, CA). Samples with >12% nonviable cells were excluded (one sample). Cells were stimulated with a pool of 15 overlapping CMV pp65 peptides (2?g/ml of each.