Nixon, D. | Search bioRxiv

bioRxiv2023

Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states

Human endogenous retroviruses (HERVs), the remnants of ancient viral infections embedded within the human genome, and long interspersed nuclear elements 1 (LINE-1), a class of autonomous retrotransposons, are silenced by host epigenetic mechanisms including DNA methylation. The resurrection of particular retroelements has been linked to biological aging. Whether the DNA methylation states of locus specific HERVs and LINEs can be used as a biomarker of chronological age in humans remains unclear. We show that highly predictive epigenetic clocks of chronological age can be constructed from retroelement DNA methylation states in the immune system, across human tissues, and pan-mammalian species. We found retroelement epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, responsive to antiretroviral therapy, and accurate in estimating long-term culture ages of human brain organoids. Our findings support the hypothesis of epigenetic dysregulation of retroelements as a potential contributor to the biological hallmarks of aging.

immunology↗

bioRxiv2018

Age but not disease progression defines CD4+ and CD8+ T stem cell memory levels in human retroviral infections: contrasting effects of HTLV-1 and HIV-1

BackgroundHuman CD4+ and CD8+ stem cell memory T cells (TSCM) represent a minor fraction of circulating lymphocytes characterized by stemness and long-term in vivo persistence. CD4+ TSCM are preferentially infected and constitute a reservoir for HIV-1, whereas CD8+ TSCM appear to play a protective role. However, little is known about CD4+ and CD8+ TSCM in the only other human pathogenic retroviral infection, human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is the etiological agent of both Adult T-cell Leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraperesis (HAM/TSP), a neuroinflammatory disorder. In ATL, CD4+ TSCM cells were identified as the hierarchical leukemic stem cell, but data in HAM/TSP are lacking. Age is a major risk factor for both ATL and HAM/TSP, as both diseases generally manifest several decades after infection. Therefore, we explored a possible link between TSCM, age and disease status in human retroviral infections in a cross-sectional study, using multiparametric flow cytometry.\n\nResultsWe found that CD4+ or CD8+ TSCM levels (quantified as CD3+CD45RA+CD45RO- CD27+CCR7+Fashi) do not differ between healthy controls and untreated HTLV-1 infected individuals with and without neuroinflammatory disorder. However, we found both TSCM as well as CD8+ TSCM significantly accumulated with age, resulting in a >400% increase in elderly HTLV-1 infected individuals (>60 years). A significant correlation between age and TSCM signature genes was validated at the transcriptome level in an independent cohort. CD8+ but not CD4+ TSCM were significantly decreased in untreated HIV-1 infection. Unexpectedly, CD8+ TSCM recovery upon successful antiretroviral treatment was essentially complete (92.2{+/-}11.0%) in younger (<45 years) individuals, but significantly lower (37.3{+/-}6.1%) in older (>45 years) individuals (p=0.0003).\n\nConclusionIn HTLV-1 infection, an age-dependent accumulation of CD4+ and CD8+ TSCM points towards a possible protective role of CD8 TSCM in the elderly against leukemic but not neuroinflammatory disease. HIV-1-infected individuals lose their ability to restore CD8+ TSCM levels upon successful antiretroviral therapy at later age (>45 years), which might eventually lead to immunological failure and decreased vaccine efficacy.

immunology↗