Early immune senescence in HIV disease

Abstract

Non-AIDS-defining co-morbidities that occur despite viral suppression and immune reconstitution using antiretroviral therapy depict early aging process in HIV-infected individuals. During aging, a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells, translates into a general decline of the immune system, gradually leading to immunosenescence. Inflammation is a hallmark of age-associated comorbidities, and immune activation is a hallmark of HIV disease. Constant stimulation of the immune system by HIV or due to co-infections activates the innate and adaptive immune system, resulting in release of mediators of inflammation. Immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease. Dysfunctional thymic output, along with HIV-mediated disruption of the gastrointestinal barrier leading to microbial translocation, contributes to the circulating antigenic load driving early senescence in HIV disease.

Figure 1

Accelerated aging model in HIV infection. Viral replication results in release of virions (infectious and noninfectious HIV) into circulation. Residual ongoing replication continues to activate immune cells despite highly active antiretroviral therapy. Microbial translocation adds to the antigenic burden. Loss of thymic function alters T-cell homeostasis. Immune activation due to circulating antigen is the central event in the senescent pathway. Activated cells undergo clonal expansion in response to the persistent antigen, resulting in differentiation and accumulation of nonfunctional end stage senescent cells. Activated cells release inflammatory mediators, causing optimal and suboptimal inflammation associated with non–AIDS-defining co-morbidities and premature aging.