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Cytomegalovirus (CMV) infection exerts an enormous effect on human immunity, as it is associated with an immune-impaired response, a variety of chronic diseases, and overall survival in elderly individuals. Levels of anti-CMV antibodies may be associated with the differentiation degree of T cell subsets. Titers are significantly higher in the elderly and positively correlated with specific CD4؉ T cell responses to CMV. In the elderly, antibody titers are associated with the degree of differentiation and the T cell receptor excision circle (TREC) content in CD4؉ T cells, with other features of the immune risk profile, and with a reduced ability to respond to immunization in vivo. Associations may be absent in young subjects because their anti-CMV antibody titers are lower than those of the elderly. However, comparing young and elderly individuals with similar antibody levels reveals differences in their highly differentiated and naïve T cells. These are more marked in individuals with high titers. In parallel with the increase in anti-CMV antibodies, the elderly experience a significant reduction in absolute counts of naïve CD4؉ T cells, which may be a strategy to compensate for the expansion of differentiated cells and to avoid an increase in total T cells. In summary, our results show that titers of anti-CMV antibodies, and not only CMV seropositivity, are related to differentiation status and immunocompetence in the elderly, making this as an important prognostic marker of the status of immune system function.T he betaherpesvirus cytomegalovirus (CMV) is a persistent activating virus that primarily resides in the myeloid cell compartment but also spreads to other cell types. Clinically, infection is considered essentially asymptomatic in immunocompetent hosts. However, immunosuppressed individuals may suffer serious consequences as a result of viral reemergence. After infection, the virus establishes lifelong latency within the host and periodically reactivates. Reactivation from latency is a key step in the pathogenesis of the infection and can be detected in response to inflammation, infection, stress, or immunosuppression (1, 2). Activation of protein kinase C and NF-B by tumor necrosis factor alpha (TNF-␣) and increasing concentrations of cyclic AMP by stress hormones and prostaglandins promote viral reactivation and replication. Reactivation of CMV is more frequent in the elderly, as demonstrated by the direct detection of CMV DNA in the urine. Although reactivation is frequent in the elderly, it is subclinical in nature (3).Recently, CMV has been linked to a variety of chronic diseases with an inflammatory component, including cardiovascular diseases, cancer, and cognitive and functional impairment (4-7). The specific mechanisms responsible for these associations have not been fully determined but are likely to have an inflammatory and immune component. Reactivation may result in increased levels of proinflammatory molecules such as interleukin 6 (IL-6), TNF-␣, and C-reactive protein (CRP). In fact, CMV ...

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HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.

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