HIV reservoir and premature aging: risk factors for aging-associated illnesses in adolescents and young adults with perinatally acquired HIV

Despite receiving antiretroviral therapy (ART), an increasing number of adolescents and young adults with perinatally acquired HIV (PHIVAYA) are at risk of developing premature senescence and aging-associated illnesses, including cancer. Given this concern, it is crucial to assess aging biomarkers and their correlation with the HIV reservoir in order to comprehensively characterize and monitor these individuals. Fifty-five PHIVAYA (median age: 23, interquartile range [IQR]: 20-27 years, and 21 [18-23] years on ART at the time of study sampling) were studied along with 23 age-matched healthy controls. The PHIVAYA exhibited significantly higher percentages of activated, senescent, exhausted CD4 and CD8 T cells, shorter telomeres, reduced thymic output, and higher levels of circulating inflammatory markers (PAMPs, DAMPs, and pro-inflammatory cytokines IL-6, IL-8, and TNF alpha) as well as denervation biomarkers (neural cell adhesion molecule 1 [NCAM1] and C-terminal Agrin fragment [CAF]), compared to controls. HIV-DNA levels positively correlated with activated, senescent, exhausted CD4 and CD8 T cells, circulating biomarkers levels, and inversely with regulatory T and B cells and telomere length. According to their viremia over time, PHIVAYA were subgrouped into 14 Not Suppressed (NS)-PHIVAYA and 41 Suppressed (S)-PHIVAYA, of whom 6 who initiated ART within one year of age and maintained sustained viral suppression overtime were defined as Early Suppressed (ES)-PHIVAYA and the other 35 as Late Suppressed (LS)-PHIVAYA. ES-PHIVAYA exhibited significantly lower HIV-DNA reservoir, decreased percentages of senescent and exhausted CD4 and CD8 T cells, reduced levels of circulating inflammatory and denervation biomarkers, but longer telomere compared to LS- and NS-PHIVAYA. They differed significantly from healthy controls only in a few markers, including higher percentages of regulatory T and B cells, and higher levels of DAMPs. Overall, these results underscore the importance of initiating ART early and maintaining viral suppression to limit the establishment of the viral reservoir and to counteract immune and cellular premature aging. These findings also suggest new approaches for minimally invasive monitoring of individuals at high risk of developing premature aging and age-related illnesses.The introduction of combined antiretroviral therapy has led to the transition of HIV perinatally infected children into adolescence and young adulthood, thereby increasing their susceptibility to aging-related diseases, including cancer. While previous studies have examined aging markers in individuals living with HIV, no study has comprehensively integrated multifaceted features of aging in adolescents/young adults with perinatally acquired HIV (PHIVAYA). In this study, we conducted a comprehensive evaluation of a multiparametric aging profile, including immunophenotypic aspects (activated, senescent and exhausted T and B cells), cellular markers (telomere length and thymic output), circulating inflammatory (PAMPs, DAMPs, cytokines) and denervation (CAF and NCAM1) biomarkers. Our findings demonstrate that aging biomarkers in PHIVAYA were altered compared to age-matched controls and were correlated with HIV-DNA reservoir levels. Importantly, PHIVAYA with early and sustained viral suppression exhibited levels of most aging biomarkers comparable to those of controls. The insights from this study have the potential to significantly impact healthcare strategies and improve the well-being of these individuals.