Ari Bitnun1, Doris G Ransy2, Jason Brophy3, Fatima Kakkar4, Michael Hawkes5, Lindy Samson3, Bayader Annabi2,6, Amélie Pagliuzza7, Jacob-Adams Morand2,6, Laura Sauve8, Nicolas Chomont6,7, Stephanie Lavoie9, John Kim9, Paul Sandstrom9, Paul A Wender10, Terry Lee11, Joel Singer11,12, Stanley E Read1, Hugo Soudeyns2,6. 1. Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario. 2. Centre de Recherche du Centre Hospitalier Universitaire (CHU) Sainte-Justine, Montreal, Quebec. 3. Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ontario. 4. Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Quebec. 5. Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton. 6. Department of Microbiology, Infectiology & Immunology, Université de Montréal, Quebec. 7. Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Quebec. 8. Oak Tree Clinic, Women's Hospital and Health Centre of British Columbia, Department of Pediatrics, University of British Columbia, Vancouver. 9. National Human Immunodeficiency Virus (HIV) & Retrovirology Laboratories, Public Health Agency of Canada, Winnipeg, Manitoba, Canada. 10. Department of Chemistry and Department of Chemical and Systems Biology, Stanford University, California. 11. Canadian Institutes of Health Research Canadian HIV Trials Network, Vancouver, British Columbia. 12. School of Population and Public Health, University of British Columbia, Vancouver, Canada.
Abstract
BACKGROUND: The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus-1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years. METHODS: HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO). RESULTS: Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09). CONCLUSIONS: The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection.
BACKGROUND: The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus-1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years. METHODS:HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO). RESULTS: Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09). CONCLUSIONS: The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection.
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