Now that we are more than 25 years into the HIV epidemic, there are many more HIV-infected individuals of older age due to improvements in antiretroviral therapy. From 2000 to 2004, the Centers for Disease Control reported that the proportion of AIDS patients who are ≥ 50 years of age rose from 19% to 27% and that the number of adults ≥ 50 years of age living with HIV infection and/or AIDS more than doubled. Importantly, for that surveillance period, persons 40 to 49 years of age had the highest prevalence of HIV/AIDS and the steepest rise in prevalence. The number of older people with HIV/AIDS is expected to increase even further during the next decade. It is projected that by 2015, more than half of all HIV-infected individuals in the United States will be over the age of 50 years [1
]. Adults with HIV on prolonged treatment with highly active antiretroviral therapy (HAART) frequently experience long-term side effects of disease and treatment that mimic natural aging processes.
Increasing evidence suggests that HIV-1–infected individuals experience similar immunologic changes as uninfected elderly persons. An increasing number of investigators have reported osteoporosis [2
], atherosclerosis [3
], and neurocognitive decline [4
] in HIV-1–infected patients, and HIV-1 disease progression is also associated with onset of frailty usually related to old age [5
]. Thus, physiologic alterations and co-morbidities suggest that advanced aging occurs in HIV disease. Several immunologic alterations that characterize HIV-1–infected individuals are remarkably similar to those associated with age in the HIV-1–uninfected elderly. During aging, a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells with shortened telomeres, occurs. It is thought that these changes are a consequence of immune activation and inflammation, which translates into a general decline of the immune system, gradually leading to immunosenescence (aging of the immune system) [6
]. This article examines accelerated aging in HIV disease as an activation-induced inflammatory condition that is a consequence of optimal or suboptimal inflammation and activation due to antigen- (infectious or noninfectious HIV) driven injury that occurs over the lifetime, rather than just a complex group of diseases or morbidities associated with age or HIV infection. The use of an integrated strategy to control activation and inflammation rather than treat individual diseases is likely the modality to control advanced aging in the HIV-infected individual.
Immune activation is a hallmark of chronic HIV infection. Immune activation occurs despite effective HIV control with HAART and is a critical factor contributing to HIV pathogenesis [7
]. Activation and inflammation due to persistent infection such as HIV also provide a milieu for accelerated replicative senescence of T cells that progressively accumulate during the normal course of aging [8
]. HIV infects CD4 T cells, the profound depletion of which results in immunodeficiency and terminal AIDS. Immune activation is postulated to be the leading cause associated with non–AIDS-defining co-morbidities [9
]. Whether these non–AIDS-defining co-morbidities would occur despite the control of ongoing HIV replication with antiretroviral therapy or whether they are an outcome of an aging immune system is currently under investigation. Whether HIV alone drives immunosenescence or if there are alternative pathways that contribute to early aging in HIV-infected individuals also remains to be examined. First and foremost, more than 99% of HIV-1 particles detected in the circulation are not productively infectious virions [10
]. These noninfectious particles contribute to HIV-induced immunopathogenesis, as they activate the innate [11
] and adaptive [12
] immune system to release mediators of inflammation that are known to be associated with age-associated co-morbidities. The proof of this concept comes from data from the Strategies for Management of Antiretroviral Therapy (SMART) study, where elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were found to be associated with non–AIDS-defining co-morbidities in HAART-suppressed patients [13
]. The persistence of HIV virions, infectious or noninfectious, in the circulation results in the constant stimulation of the immune system and likely drives early senescence in HIV infection.
Secondly, alterations in immune homeostatic mechanisms may lead to progressive loss of the naïve and memory T-cell pool, resulting in an imbalance in T-cell phenotypes. Altered T-cell homeostasis impairs regulatory cell function. HIV may deplete regulatory CD4+ T cells, which are normally responsible for suppressing T-cell activation and limiting the amount of inflammatory damage to tissues [14
]. Excessive production and/or accumulation of proinflammatory mediators such as TNF-α, IL-1β, and IL-6 in HIV infection and in the elderly suggests that immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease. Finally, direct activation of innate immune cells by HIV and by disruption of the gastrointestinal barrier due to HIV-mediated depletion of Th-17 cells, leading to microbial translocation, could be contributing factors to activation and inflammation in the accelerated aging process.