Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection

Abstract

The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein-Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2(HSV-1/2), and Varicella-Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections.

Keywords: EBV; HBV; HCV; HDV; HHV-8; HIV; HPV; HSV; HTLV; VZV; exhaustion; senescence; telomerase; telomere.

Figure 1

The relationship between host immune response and the invading virus during the course of acute or chronic viral infection. During acute viral infection, the balance swings in favor of viral production, leading to the expression of viral genes and rapid viral replication. The conclusion often involves either host death (enhanced viral replication; dotted blue line) or viral clearance (enhanced immune response; dotted red line). The latter involves a robust immune effector response from CD4+ and CD8+ T cells and the development of immune memory. During chronic viral infections, there is a balance between virus replication and host immune response, leading to persistence of the virus. On the part of the virus, this often involves suppression of viral lytic genes in favor of viral latency genes. The immune response is often impaired, due to a reduction in host adaptive immune responses and chronic T-cell exhaustion. Chronic viral infections are categorized as either slow, latent, or productive, depending upon the timing of virus replication and the resolution of disease. (Abbreviations: EBV, Epstein–Barr Virus; HBV/HCV/HDV, Hepatitis B/C/D virus; HHV-8, human herpesvirus 8; HIV, human immunodeficiency virus; HPV, Human papillomavirus; HSV-1/2, herpes simplex virus-1/2; HTLV-1, Human T-cell leukemia virus type I; BKV, BK virus; and JCV, John Cunningham virus).

Figure 2

Telomere attrition and the DNA damage response during chronic viral infection. During an initial viral encounter, a robust T-cell response occurs followed by telomerase activation and retention of telomere lengths. Subsequent antigen encounters lead to inactivation of the telomerase promoter and loss of telomerase expression. Telomere attrition, caused by chronic exposure to viral antigen, is exacerbated over time (dotted arrows). Enduring hyper-antigenemia results in telomere crisis and the activation of the DNA damage signal. This results in T-cell exhaustion, inhibition of T-cell proliferation, and cell cycle arrest. The eventual outcome is programmed cell death (apoptosis) or replicative senescence. (Abbreviations: ATM, ATM Serine/Threonine Kinase; ATR, ATR Serine/Threonine Kinase; CDC25a, Cell Division Cycle 25A; CHUK-1/2, Conserved Helix-Loop-Helix Ubiquitous Kinase-1/2; H2AX, H2A Histone Family Member X; p16, Cyclin Dependent Kinase Inhibitor 2A; p21, Cyclin Dependent Kinase Inhibitor 1A; p53, Tumor Protein P53; and Rb, Retinoblastoma 1)

Figure 3

A depiction of T-cell exhaustion during chronic viral antigen exposure. Initial viral encounter leads to rapid activation of host adaptive immunity. A robust CD8+ (red cells) and CD4+ T-cell (blue cells) response occurs, leading to activation (arrows) of immune cytokines (IFN-γ, IL-2, and TNF), proliferation of host immune effector cells (CD4+ and CD8+ T cells, and the activation of macrophages (green cells), natural killer cells, etc), generation of virus-specific memory (responsive to IL-7 and IL-15), and clearance of the invading viral pathogen (increases in perforin and granzymes, for example). Long-term exposure to virus or viral antigen leads to a step-wise decrease in effector cytokines and, over time, the appearance of T cells displaying hallmarks of exhaustion. This includes the up-regulation of inhibitory markers on the surface of the T cell (PD-1, LAG-3, CD160, TIM-3, CTLA-4, and BTLA), a differential loss (IL-2, TNF, and IFN-γ) or gain (IL-10, IL-6, and TGF-β) in cytokine expression, impaired CD8+ and CD4+ T-cell effector response, and impaired memory T cells that are no longer responsive to IL-7 or IL-15. Eventually, this can lead to T-cell senescence and/or apoptosis, rapid viral replication, and disease. (Abbreviations: BTLA, B- and T-Lymphocyte-Associated Protein; CD160, Natural Killer Cell Receptor BY55; CTLA-4, Cytotoxic T-Lymphocyte-Associated Protein 4; INF-γ, interferon-gamma; IL-2, interleukin-2; IL-6, interleukin-6; IL-7, interleukin-7; IL-10, interleukin-10; IL-15, interleukin-15; LAG-3, Lymphocyte Activating 3; PD-1, Programmed Cell Death 1; TGF-β, Transforming Growth Factor β; TIM-3, T-Cell Immunoglobulin Mucin Family Member 3; and TNF, tumor necrosis factor). Arrows show the increase/decrease of cytokine release during antigen exposure and the directionality of the immune response.