Sero-prevalence, sociodemographic factors and T cell responses specific to human cytomegalovirus

Date of Award

1-1-2018

Degree Type

Thesis

Degree Name

PhD in Health Sciences

Department

Biological and Biomedical Sciences

Abstract

Human cytomegalovirus (HCMV) infection is found widely around the globe. Its sero-prevalence varies from 30-90% in most countries, which increases with age and lower socio-economic status. Reliable data on HCMV-IgG and IgM sero-prevalence and HCMV-associated immunobiology are not available for Karachi, Pakistan. Objectives: This project aimed to determine HCMV-IgG, IgM seroprevalence and identify sociodemographic factors associated with HCMV seropositivity. The characteristics of HCMV-specific T cells with ageing and anti-HCMV IgG titre in HCMV sero-positive individuals were also examined. Methodology: Sero-prevalence and associated sociodemographic factors were determined in a total of 1000 individuals (>18 years) that were interviewed and tested for HCMV-specific IgG and IgM antibodies. T cells stimulated in-vitro against HCMV-derived proteins in 32 healthy adults (24-65 years) were analysed by a multiparametric flow cytometry assay and correlated with age and IgG titre. Results: Sero-prevalence of HCMV-IgG and IgM was 93.2 and 4.3%, respectively. Age (p=0.002), gender (p=0.001), crowding index (p=0.003), education (p< 0.001), income (p=0.008), marital status (p=0.008) and sampling location (p< 0.001) were significantly associated with HCMV-IgG sero-prevalence. Seroprevalence of HCMV-IgM was found to be significantly associated with decreasing household size (p=0.008). The logistic regression model demonstrated increasing age (Odds Ratio [OR] = 3.95; 95% Confidence Interval [Cl]: 1.79-8.71), female gender (OR = 1.89; 95% CI: 1.10-3.25) and decreasing income (OR = 0.72; 95% CI: 0.54- 0.96) as independent predictors of HCMV-IgG sero-positivity. CD8+ T cell responses against pp65 (0.07-9.8%), 1E1 (0.03-48.1%), pp50 (0.6- 6.9%) and UL28/UL23/UL24/UL33 (0.06-13.9%), whereas, CD4+ T cell responses against lysate (0.05-8.6%), pp65 (0.02-2.2%) and gB/gH (0.02-4.1%) were observed at varying magnitude. Age correlated with reduced naïve (r, = -0.681; p< 0.0001) and early differentiated cells (r, = -0.374; p=0.035); and increased late differentiated cells (r3 = 0.407; p=0.021) in the CD8+ T cell compartment. Age was not correlated with HCMV-specific CD8+ and CD4+ T cell responses except 1E1-specific CD8+ response (r, = 0.471; p=0.049). T cell responses displayed age-dependent reduction of naïve (lEl-specific CD8+ cells: rs = -0.62; p=0.014, HLA-A restricted epitope-specific CD8+ cells: r, = -0.536; p=0.039, pp65-specific CD4+ cells: r, = -0.449; p=0.02) and accumulation of late differentiated cells (HLA-C restricted epitope-specific CD8+ cells: rs = 0.7; p=0.036). CD4+ TEi (r, = 0.441, p=0.012) and CD8+ revertant effector memory (rs "- 0.538, p=0.002) subsets were positively correlated with anti-HCMV 1gG titre. Interestingly, IgG titre displayed positive correlation with lysate-specific (r, = 0.371; p=0.037) and pp65-specific (r, = 0.4098; p=0.034) CD4+ T cells and these responses were predominantly of the TEM phenotype (Lysate-specific CD4+: r, = 0.509; p=0.004, pp65-specific CD4+: rs = 0.561; p=0.004). Conclusions: Sero-prevalence of HCMV in the study population is high. The IgM sero-positivity observed in small households (1-3 individuals) could have resulted from a recurrent HCMV infection. The magnitude of HCMV-specific T cell responses appears to remain stable across 24-65 years of age in population studied and immune alterations in the T-cell compartment may be evident in HCMVseropositive individuals. Elevated anti-HCMV IgG titre and increased differentiated T cells observed in the study population could indicate potential susceptibility to early immunosenescence.

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