Cytomegalovirus, aging, and HIV: a perfect storm

The success of highly active antiretroviral therapy in preventing progression of HIV-infected individuals to AIDS has greatly reduced the burden of opportunistic infections. Individuals with HIV infection are living longer, but as a group are at greater risk to develop age-related disorders, such as certain cancers, cardiovascular disease, type II diabetes, and cognitive impairment, at earlier ages than non-HIV-infected persons. This premature susceptibility to age-related morbidities reflects a syndrome referred to as accelerated aging, wherein deleterious features associated with aging emerge decades earlier in the setting of chronic HIV infection. A prominent immunological feature of accelerated aging in HIV infection is inflation of cytomegalovirus-specific memory T-cell responses to levels associated with an immune risk phenotype. In the absence of HIV infection, immune risk phenotypes develop in cytomegalovirus-infected octogenarians and signify some degree of immune senescence and an elevated risk for all-cause mortality. Chronic inflammation is a probable factor in health risks conveyed by the immune risk phenotype and in putative relationships between cytomegalovirus infection and the same set of age-related disorders arising in chronic HIV infection. Most HIV-infected individuals are cytomegalovirus-seropositive, both HIV and cytomegalovirus are associated with inflammation-related morbidities, and HIV infection accelerates the development of cytomegalovirus-dependent immunological abnormalities. Therefore, closer investigation of the relationship between cytomegalovirus and age-related morbidities emerging in chronic HIV infection appears warranted. This review summarizes evidence that cytomegalovirus could be an important cofactor in the development of age-related morbidities in HIV infection and discusses research to address underlying mechanisms.