Impact of Persistent Cytomegalovirus Infection on Dynamic Changes in Human Immune System Profile

Abstract

Human cytomegalovirus (HCMV) imprints the immune system after primary infection, however its effect during chronic infection still needs to be deciphered. In this study we report the variation of blood cell count along with anti-HCMV IgG and T cell responses to pp-65 and IE-1 antigens, that occurred after an interval of five years in a cohort of 25 seropositive healthy adults. We found increased anti-viral IgG antibody responses and intracellular interferon-gamma secreting CD8+ T cell responses to pp-65: a result consistent with memory inflation. With the only exception of shortage in naive CD8+ T cells most memory T cell subsets as well as total CD8+ T cells, T cells, lymphocytes, monocytes and leukocytes had increased. By contrast, none of the cell types tested were found to have increased in 14 subjects stably seronegative. Rather, in addition to a shortage in naive CD8+ T cells, also memory T cell subsets and most other cell types decreased, either in a statistically significant or non-significant manner. The trend of T cell pool representation with regard to CD4/CD8 ratio was in the opposing directions depending on HCMV serology. Globally, this study demonstrates different dynamic changes of most blood cell types depending on presence or absence of HCMV infection. Therefore, HCMV plays a continual role in modulating homeostasis of blood T cells and a broader expanding effect on other cell populations of lymphoid and myeloid origin.

Fig 1. Description of the study.

Follow-up times and characteristics of the HCMV-seropositive subjects (A) and of the HCMV-seronegative subjects (B).

Fig 2. Follow-up of HCMV-specific responses.

(A) Unit variation of the HCMV-specific IgG Ab between the first and the second time point of the follow-up. (B) Number variations of anti-pp65 and anti-IE-1 CD4 and CD8 T cell responses, evaluated as differences in intracellular IFN-γ positive T cells after stimulation of freshly isolated PBMCs with HCMV synthetic peptides, between the first and the second time point of the follow-up. (C) Levels of HCMV-specific IgG Ab at the two time points of the follow-up. (D) Absolute numbers of HCMV-specific CD4 and CD8 T cell responses at the two time points of the follow-up. In all the panels the individual variations are shown in individual subjects sorted with ascending order of age. In panels C and D, the box plots show the median, 25^th and 75^th percentiles, and range. The Wilcoxon signed-rank nonparametric tests were used to derive p values.

Fig 3. Follow-up of T cells and white blood cells numbers in peripheral blood of HCMV-seropositive subjects.

(A) Absolute numbers of naïve, central memory (CM) and effector memory (EM), among CD4+ and CD8+ T cells at the two time points of the follow-up. (B) Absolute numbers of total CD4+, total CD8+, ratio CD4:CD8 and total CD3+ at the two time points of the follow-up. (C) Absolute numbers of leukocytes, monocytes, neutrophils and leukocytes at the two time points of the follow-up. In all panels, the box plots show the median, 25^th and 75^th percentiles, and range. The Wilcoxon signed-rank nonparametric tests were used to derive p values.

Fig 4. Follow-up of T cells and white blood cells numbers in peripheral blood of HCMV-seronegative subjects.

(A) Absolute numbers of naïve, central memory (CM) and effector memory (EM), among CD4+ and CD8+ T cells at the two time points of the follow-up. (B) Absolute numbers of total CD4+, total CD8+, ratio CD4:CD8 and total CD3+ at the two time points of the follow-up. (C) Absolute numbers of leukocytes, monocytes, neutrophils and leukocytes at the two time points of the follow-up. In all panels, the box plots show the median, 25^th and 75^th percentiles, and range. The Wilcoxon signed-rank nonparametric tests were used to derive p values.