Profound immune consequences for young adults infected with HIV perinatally or during childhood

Antiretroviral therapy (ART) has rendered what was once a deadly diagnosis into a manageable, tolerable disease. HIV-infected people are now living long enough to age with the virus and have life expectancies approaching that of the uninfected population. Despite these advances, people living with HIV are plagued with disorders that are typically associated with aging, including neurocognitive, metabolic, cardiovascular disorders, and other non-AIDS-defining comorbidities [1]. This occurs, in part, because of the persistent taxing of the immune system that occurs when fighting a chronic illness. In fact, viral persistence in the face of ART has been explained by viral latency, lowered effectiveness of drugs in some anatomical sites/cell types, and cell-to-cell spread of the virus [2,3]. As a result, antigen persistence due to HIV-1 infection promotes chronic immune activation, cellular senescence, and lymphopoiesis that result in an inflammatory state termed ‘inflammaging’, a concept that attributes a proinflammatory milieu to the aging process [4]. This premature accelerated aging of the immune system has been evaluated most comprehensively in adults living with HIV. However, adults are not the only population susceptible to this ‘inflammaging’ profile. Indeed, adolescents and young adults who were infected with HIV at birth or during childhood (YAHIC) are an important population to consider. The current immunological and virological status of youths perinatally or during childhood infected with HIV and their covariables have not been well investigated. Some studies suggested that YAHIC may benefit from their robust immune cells regeneration capacity and therefore avoid the deleterious effects of HIV-1 associated immune-aging phenomenon [5]. Despite their relatively young age, and a presumed prime immunologic state their biologic age confers, YAHIC can be particularly susceptible to an advanced aging profile due to the long-term stress of mounting an antiviral response for the majority of their lives. The study by Fastenackels et al.[6] beautifully addresses this understudied population by examining the impact of HIV infection on the immune system of YAHIC, focusing specifically on CD34+ hematopoietic progenitor cells, T-lymphocytes, B-lymphocytes, and natural killer (NK)-lymphocytes, and naïve or differentiated CD4+ and CD8+ T cells. Fastenackels et al.[6] noted profound alterations in the frequencies of all examined immune subsets, as compared with age-matched, uninfected individuals [6]. YAHIC had decreases in CD4+/CD8+ ratios, B, NK, and CD34+ progenitor cells, as well as both naïve and effector/memory CD4+ and CD8+ T cells. Collectively, these findings are indicative of a state of immune senescence in YAHIC, reflective of the toll of HIV on the lymphocytic immune compartment. Importantly, Fastenackels et al.[6] also included a comparative analysis of the same immune parameters for elderly, uninfected individuals. Despite their young age (between 18 and 25 years), the frequencies of all examined immune components were similar between YAHIC and those who were more than 65 years old. A major strength of the study, this analysis demonstrated that the immune senescence that occurred in YAHIC was a result of a premature immune aging profile, wherein the young adults were immunologically reminiscent of much older individuals [6]. In this particular study, Fastenackels et al. [6] also included an analysis of middle-aged, individuals who were infected with HIV during adulthood. Similar to the older HIV-infected individuals, YAHIC had decreased frequencies of all examined immune components. However, there was a striking difference between the two populations: the older HIV-infected individuals had complete viral suppression in plasma, whereas persistent viral replication occurred in an unexpected high proportion of the YAHIC. This viremia was associated with CD4+ T-cell depletion, elevated serum levels of high-sensitivity C-reactive protein, higher frequency of activated CD8+ T cells and inversely correlated with CD4+/CD8+ ratios, indicating that hyper immune activation and declining immunity were occurring in the YAHIC. Together, the major finding of this study identified sustained viral replication as the driving force of the premature immune aging profile in YAHIC. In contrast, premature immunologic aging likely occurs as a result of chronic, but well controlled, HIV infection for those infected during adulthood. The finding indicates a substantial opportunity for intervention for YAHIC for increased adherence to their prescribed ART regiments. Noncompliance to these life-saving therapies is not only required for suppression of the virus, it is also protective against potentially irreversible damage to the lymphopoietic system and premature immunosenescence. Therefore, the findings from this study should serve as substantial evidence to convince HIV-infected youths to adhere to ART recommendations to prevent seeding of the HIV reservoir and accelerated inflammaging. Acknowledgements Conflicts of interest There are no conflicts of interest.

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