Accelerated Aging in HIV/AIDS: Novel Biomarkers of Senescent Human CD8+ T Cells

Abstract

Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART) is largely based on CD4+ T cell counts and viral load, measures that fail to take into account the CD8+ T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase (ADA), glucose uptake receptor 1 (GLUT1), and leucine-rich repeat neuronal 3 (LRRN3) to CD38 expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced ADA, telomerase activity and LRRN3 gene expression were significantly associated with high CD38 and HLA-DR in CD8+ T cells, with % ADA+ cells being the most robust predictor of CD8+ T cell activation. Our results suggest that ADA, LRRN3 and telomerase activity in CD8+ T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8+ T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8+ T cells, the prolonged survival and resultant increased age of the HIV+ population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.

The sbv IMPROVER Systems Toxicology computational challenge: Identification of human and species-independent blood response markers as predictors of smoking exposure and cessation status

“…Further blood cell type-specific investigations may provide a deeper understanding of the contribution of each sub-population to the smoking signature. For example, among the genes with the strongest association with smoking, P2RY6 , PID1 , and SASH1 were identified in the transcriptome of monocytes, and LRRN3 may be expressed specifically in T lymphocyte sub-population [53, 54]. Regarding the consensus species-independent smoking signature, species-specific regulation mechanisms and/or blood cell population composition may account for the opposite directionality of expression changes observed in human and mouse for a subset of the genes.…”

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

“…Impaired telomerase activity and modulation of other biomark ers, including inhibition of adenosine deaminase, which works by converting immunosuppressive adenosine to inosine, have been strongly associated with an increase in CD38, a marker of T cell activation as well as of HIV disease progression in CD8+ T cells [91, 92]. Moreover, adenosine inhibits IL-2 production, accelerates the loss of CD28, and contributes to the inhibition of telomerase activity [93].…”

The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length

“…13 Recent evidence demonstrated a relevant role of ADA in replicative senescence through its capacity of modulating TA. 4,5 Moreover, we recently reported the association between the functional ADA rs73598374 and human life expectancy. 8,9 In the present work we provided first evidence for the association of ADA rs73598374 with TA and LTL.…”

“…4 Notably, a recent study further underscores the impact of ADA on replicative senescence by showing a significant correlation of CD8 þ T-cell TA with the percentage of CD8 þ T cells that were ADA þ in HIV-1 þ individuals. 5 The ADA gene displays a G4A single-nucleotide polymorphism (SNP, rs73598374, NM_000022.2:c.22G4A) at nucleotide 22 of exon 1 leading to an Asp (allele 1*) to Asn (allele 2*) amino-acid substitution at position 8 of the mature protein (NP_000013.2:p. Asp8Asn) that influences ADA activity. ADA rs73598374-A displays an B35% lower activity than that of the ADA rs73598374-G and, consequently, carriers of ADA rs73598374-A show a higher level of both circulating and intracellular adenosine.…”