**2.6 Human cytomegalovirus (CMV) reactivation and CMV-specific CTLs**

CMV is a highly prevalent herpes virus that is chronically carried by more than 70% of the world's population (Rawlinson, 1999). It appears to be the most immunodominant antigen confronted by a carrier's immune system throughout life. The primary CMV infection usually occurs early in childhood, but seldom causes severe disease, and was long thought not to be a major human pathogen. However, the virus has mechanisms to evade immune surveillance and survive in an immunocompetent host. Once infected, the virus hides in the human body and the immune system is unable to eliminate it completely. A hallmark of latent CMV infection is its capacity to induce recurrent disease, mainly in immunocompromised individuals. Patients at high risk for reactivation of latent CMV include those with a human immunodeficiency virus infection, malignancies, organ transplant, or on immunosuppressive therapy (Alberola et al., 2001; Chemaly et al., 2004; Limaye et al., 2001). It has been suggested that CMV-specific effector T cells accumulate with aging in such large numbers that they may be the dominant T-cell population in the peripheral blood of healthy elderly individuals. In fact, CMV-specific CD8 T cells in such individuals may constitute as much as 50% of the entire CD8 T-cell repertoire (Khan et al., 2002).

In cancer patients, over 50% of patients on cancer chemotherapy experience CMV reactivation during the course of chemotherapy (Han, 2007; Kuo et al., 2008; Ogata et al., 2011), with the average viral load peaking after the third course of treatment (Kuo et al., 2008). Furthermore, CMV-specific IgG titers are simultaneously elevated with the increase in virus load. In addition, the clonal expansion of CMV-specific CD8 T cells is also observed in cancer patients; however, these cells are predominantly CD28-, indicating that the expanded CMV-specific T-cell clones are terminally differentiated cells, i.e., essentially hyporesponsive to CMV (Chen et al., 2010). These T cells not only suppress other memory T-cell populations through competition for space or growth factors but also reduce the overall T-cell diversity and function (Effros et al., 2005; Messaoudi et al., 2004). The adverse impact of CMV on the immune status of cancer patients, thus, may be due to the presence of clonally expanded, highly differentiated, dysfunctional CMV-specific T cells that inhibit the diversity and ability of the immune system to respond to other antigens (Wherry et al., 2007). In extensively treated patients with terminal cancer, a decrease in the population of earlydifferentiated T cells, such as naïve and TCM cells, is associated with the expansion of a CMV-specific T-cell clone. In addition, IL-7R expression of the immune cells was inversely correlated to the intracellular viral load of CMV. Following chemotherapy, CMV reactivation left a fingerprint on the T-cell population, i.e., a significantly enhanced number of circulating cytolytic T cells in CMV carriers. The clonal expansion of CMV-specific T cells may thus shrink the repertoire of immune cells available for other antigens. In fact, this may be a contributory factor to the disease progression frequently seen in cancer patients. Therefore, CMV drives the expansion of T-cell subsets that are linked with immunosenescence, which may add to the chemotherapy-associated deterioration of immune function (Messaoudi et al., 2004; Wherry et al., 2007).
