Clinical Correlates of Human Immunodeficiency Virus–1 (HIV-1) DNA and Inducible HIV-1 RNA Reservoirs in Peripheral Blood in Children With Perinatally Acquired HIV-1 Infection With Sustained Virologic Suppression for at Least 5 Years

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.

Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial

“…Furthermore, initiation of continuous ART within the first week of life in another group of HIV-infected infants [ 43 , 44 ] has been associated with more rapid HIV-1 DNA decay compared to ART-initiation at median of 7 weeks of age followed by ART-interruption (ART-96W) and ART-initiation at median 22 weeks followed by continuous ART (ART-Def). These data, and other recent studies support earlier initiation and sustained virological suppression within the first 2 years of life to most effectively reduce reservoir size [ 27 , 28 , 45 , 46 ].…”

“…Formation and stability of the HIV-1 reservoir in the presence of ART is not well understood [20][21][22], particularly whether its persistence is primarily due to longevity of latently infected cells or low-level replication [23][24][25]. Although earliest possible ART initiation is considered optimal in vertically infected children [26][27][28], it is unclear how timing of initiation, ART duration or ART-interruption within early childhood years, impacts on viral reservoirs and immune responses [29]. Further knowledge in these areas could inform practical approaches towards functional cure; yet even in the absence of a functional cure, the long-term impact of different ART-strategies on reservoir size is of considerable interest with potential to inform future ART management strategies in childhood.…”

Understanding Viral and Immune Interplay During Vertical Transmission of HIV: Implications for Cure

“…In children in the EIT study who started on ART at < 7 days of life, sustained HIV RNA suppression was associated with negative HIV serostatus and negative qualitative HIV DNA PCR at ~20 months (225). HIV seronegativity has also been described in other studies of early or very early ART and has been proposed as an estimate for reservoir size (227,228,(241)(242)(243)(244).…”

Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window

“…Previously, our group developed a practical fivestep synthesis of prostratin from phorbol (3), a readily available and sustainable natural product isolated as a major constituent of croton oil (45). As is necessary for clinical and research studies, this synthesis has allowed for facile access to large quantities of prostratin and its analogs and a lead analog has recently been used in ex vivo reservoir studies of perinatally and acutely HIV-infected children and adults, respectively (46,47). Significantly, many C13 analogs of prostratin accessible with this synthesis displayed higher potency (up to two orders of magnitude greater) than the natural product itself in binding affinity to A B C Fig.…”