Title

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

Date of Award

2018

Document Type

Thesis

Degree Name

Doctor of Philosophy in Health Science (PhD)

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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