In addition to inducing immune exhaustion that impairs essential functional activity, persistent viral infections can also lead to immune senescence, with accelerated premature aging due to telomere erosion or unrepaired DNA damage (Appay et al. 2007
; Effros et al. 2008
; Ferrando-Martínez et al. 2011
; Voehringer et al. 2001
). In the aging process, ataxia telangiectasia Rad3-related (ATR) and ataxia telangiectasia mutated (ATM) kinases are activated by double strand breaks in DNA or chromatin disruption (Sancar et al. 2004
; Zou and Elledge 2003
), which in turn, activate the DNA damage checkpoint (Bakkenist and Kastan 2003
; Brown and Baltimore 2003
). This senescence process seems to crosstalk with the cell exhaustion signal through a cascade of intracellular regulatory proteins, leading to cell cycle arrest and poor immune responses (). It has been well-established that an age-related decline in immune responses in the elderly results in greater susceptibility to infection and reduced responses to vaccination. This decline in immune structure and function affects both innate and adaptive immune responses, and in parallel, the production of inflammatory mediators increases. The adaptive immune system depends on its proliferative capacity; however, the T cell repertoire, once established, is relatively robust to aging and only decompensates when stressed. Such stressors include chronic infections such as HCV and HIV, even when viral replication is controlled. Chronic immune activation in the presence of T cell exhaustion and DNA damage responses in these patients synergizes to develop an immune phenotype that is more characteristic of the elderly, with the declining ability of their immune system to respond to vaccines and to protect from infection (LeSaux et al. 2012).
A putative scheme suggesting that immune exhaustion and immune senescence signaling block over-activated helper T cell progression through distinct but cross-linked pathways
Accumulating evidence suggests that cells of the immune system may have a limited lifespan in vivo following repeated antigenic stimulation. In this context, persistent activation during chronic HIV and/or HCV infection may lead to an exhaustion as well as senescence of immune resources. This may occur at two levels: clonal (virus-specific suppression) and global (general immune suppression). Some virus-specific T lymphocytes start expressing senescence markers (CD57, p16ink4a, KLRG-1, loss of CD28) soon after primary infection. Persistently activated, virus-specific T cell clones may eventually reach stages of senescence and disappear through cell apoptosis, resulting in the loss of antigen-specific CD4+ and/or CD8+ T cell populations important to controlling viral replication. In addition, HIV infection is characterized by the accumulation of highly differentiated CD8+CD28− T cells over time. Along with the decline of T cell renewal capacities, this may reflect a general aging of the lymphocyte population. Similar observations have been found in non-infected elderly individuals, suggesting that premature immune senescence occurs in the setting of chronic viral infections as a result of persistent immune stimulation. Accelerated immunosenescence in the setting of HIV/HCV diseases results in an aging state that diminishes the ability of the immune system to contain virus while at the same time facilitating viral replication and spread. Clinically, these changes result in a lower capacity to respond to new infections or vaccines as well as an increased frequency of age-associated end-organ disease (e.g. cardiovascular complications, cancer, and neurologic disease) that is associated with increased morbidity and mortality.
Essential features of immune senescence include: reduced number and function of APCs in blood; reduced natural killer cell cytotoxicity; and decreased naive T and B cells with an increase in terminally differentiated lymphocytes. In particular, an accumulation of late differentiated effector/memory T cells contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens. Consequently, vaccine responsiveness is compromised in the elderly, especially frail patients, as well as virally-infected individuals. Indeed, we have recently found a significantly increased CD8+CD28− T cell accumulation in HCV-infected, HBV vaccine nonresponders versus responders (unpublished data). In the future, the development and use of markers of immunosenescence to identify patients who may have impaired responses to vaccination, as well as the use of end-points other than antibody titers to assess vaccine efficacy, may help to reduce morbidity and mortality due to chronic viral infections.
Because of the effect of aging on APC function, Treg-mediated immune suppression, reduced proliferative capacity of T cells, and other diminished immune responses, the efficacy of vaccines often wanes with advanced age. Strikingly, chronic HIV/HCV infections compress the aging process, accelerating comorbidities and frailty. A recent study demonstrated that young HIV-infected patients with less than 4 years of infection have early immune exhaustion leading to premature aging and senescence that is comparable to the elderly, suggesting virus-induced premature immune senescence associated with high rates of immune exhaustion following short-term infection (Ferrando-Martínez et al. 2011
). We have also explored the role of HCV-mediated immune exhaustion and immune senescence in HBV vaccine responses during chronic HCV infection. We found that HCV-infected individuals exhibit higher expressions of both exhaustion and senescence markers - including PD-1/Tim-3 and KLRG-1/p16ink4a
- in APC or helper T cells; this is associated with impaired cellular functions that are more significant in HBV vaccine non-responders compared to responders (unpublished data). Additionally, we have previously demonstrated that HCV arrests cell cycle progression through stabilization of p27kip1
– an inhibitor of cell cycle regulatory proteins CDK and cyclin D/E (Yao et al. 2003
). These findings have led to an intersection of the fields of virus-mediated immune exhaustion and immune senescence with regard to vaccine responses (). The mechanisms behind how HIV/HCV infection induces immune exhaustion and immune senescence, and whether these two distinct pathways interact each other during immune responses, have yet to be clearly defined but are essential for developing specific strategies to improve vaccine responses in the setting of viral infection.