The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children

Foster, Caroline; Rojo, Pablo; Zangari, Paola; Yates, Andrew J.; Cotugno, Nicola; Klein, Nigel; Luzuriaga, Katherine; Pahwa, Savita; Nastouli, Eleni; Gibb, Diana M; Borkowsky, William; Bernardi, Stefania; Cálvez, Vincent; Manno, Emma Concetta; Mora, Nadia; Compagnucci, Alexandra; Wahrén, Britta; Muñoz‐Fernández, María Ángeles; Rossi, Anita De; Ananworanich, Jintanat; Pillay, Deenan; Giaquinto, Carlo; Rossi, Paolo

doi:10.1016/s2055-6640(20)30510-0

Cited by 24 publications

(31 citation statements)

References 45 publications

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“…The objective of the current study was to generate a T cell immune signature using a computational approach to evaluate the relationships between immune activation, immune checkpoint markers, HIV-specific T cell responses and viral reservoir measurements in a cohort of long-term ART suppressed perinatally HIV-infected adolescent participants that initiated ART within 2 years of life [ 31 – 32 ]. We identified a 9-marker immune signature that was able to discriminate between perinatally infected young individuals with high and low HIV viral burden.…”

Section: Introductionmentioning

confidence: 99%

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals

et al. 2021

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The size of the latent HIV reservoir is associated with the timing of therapeutic interventions and overall health of the immune system. Here, we demonstrate that T cell phenotypic signatures associate with viral reservoir size in a cohort of HIV vertically infected children and young adults under durable viral control, and who initiated anti-retroviral therapy (ART) <2 years old. Flow cytometry was used to measure expression of immune activation (IA), immune checkpoint (ICP) markers, and intracellular cytokine production after stimulation with GAG peptides in CD4 and CD8 T cells from cross-sectional peripheral blood samples. We also evaluated the expression of 96 genes in sort-purified total CD4 and CD8 T cells along with HIV-specific CD4 and CD8 T cells using a multiplexed RT-PCR approach. As a measure of HIV reservoir, total HIV-DNA quantification by real-time PCR was performed. Poisson regression modeling for predicting reservoir size using phenotypic markers revealed a signature that featured frequencies of PD-1+CD4 T cells, TIGIT+CD4 T cells and HIV-specific (CD40L+) CD4 T cells as important predictors and it also shows that time of ART initiation strongly affects their association with HIV-DNA. Further, gene expression analysis showed that the frequencies of PD-1+CD4 T cells associated with a CD4 T cell molecular profile skewed toward an exhausted Th1 profile. Our data provide a link between immune checkpoint molecules and HIV persistence in a pediatric cohort as has been demonstrated in adults. Frequencies of PD-1+ and TIGIT+CD4 T cells along with the frequency of HIV-specific CD4 T cells could be associated with the mechanism of viral persistence and may provide insight into potential targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals

et al. 2021

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“…Children starting ART within 3 months of birth remain frequently HIV-1 seronegative after losing maternal antibodies and lack HIV-specific cellular immune responses, making them potentially more susceptible to uncontrolled viral replication when ART is interrupted [ 8 , 9 ]. Identifying factors and biomarkers, such as seronegativity, associated with limited viral reservoir size will potentially aid identification of participants for future proof-of-concept studies aimed at inducing ART-free viral remission [ 10 ].…”

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confidence: 99%

“…The CARMA study (Child and Adolescent Reservoir Measurements on Early Suppressive ART) is part of the existing EPIICAL consortium (Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life; www.epiical.org ), an international collaboration whose aim is to select promising HIV-1 therapeutic strategies and to identify candidates among perinatally HIV-1–infected children and adolescents and is described in detail previously [ 10 ].…”

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confidence: 99%

The CARMA Study: Early Infant Antiretroviral Therapy—Timing Impacts on Total HIV-1 DNA Quantitation 12 Years Later

Foster

Domínguez‐Rodríguez²,

Tagarro³

et al. 2020

Journal of the Pediatric Infectious Diseases Society

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Background Strategies aimed at antiretroviral therapy (ART)–free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). Methods Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children’s Actual Life (EPIICAL) consortium who commenced ART aged <2 years, and remained suppressed (viral load [VL] <50 copies/mL) for >5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. Results Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3–15.4) years after ART initiation. Eleven had total HIV-1 DNA <10 copies/106 PBMCs. HIV-1 DNA levels were positively associated with age and VL at ART initiation, baseline CD4%, and Western blot antibody score. Age at ART initiation presented a linear association (coefficient = 0.10 ± 0.001, P ≤ .001), the effect of VL (coefficient = 0.35 ± 0.1, P ≤ .001) noticeable >6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%. Conclusions In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy.

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“…Forty PHIV, who started ART within the first two years of life, were recruited cross -sectionally in CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART). This protocol is part of the existing EPIICAL consortium (Early treated Perinatally HIV-Infected individuals: Improving Children's Actual Life) [25]. Inclusion criteria were as follows: (1) ≥5 years of age, (2) viral suppression (<400 copies/mL) achieved in the first year of ART and maintained for at least five years, and (3) plasma viral load of <50 HIV-1 RNA copies/ mL at enrolment.…”

Section: Study Participantsmentioning

confidence: 99%

Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort)

et al. 2021

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Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated. Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), ≤6 months; late treated patients (LT), > 6 months), with at least five years of HIV-1 suppression (<40 HIV copies/mL), were collected between November 2017 and August 2018. NK phenotype and function were analysed by flow cytometry and transcriptional profile of PBMCs by RNA-Seq. HIV-1 DNA was measured by real-time polymerase chain reaction (Data were analysed by Spearman correlation plots and multivariable Poisson regression model (adjusted for baseline % CD4 and RNA HIV viral load and for age at ART start as an interaction term, either ET or LT) to explore the association between NK cell parameters and HIV reservoir modulated by age at ART start. Results: A significantly higher frequency of CD56 neg NK cells was found in LT compared with ET. We further found in LT a positive correlation of CD56 neg NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, CD107a + and IFN-c + frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally, RNA-Seq analysis showed in LT an up-regulation of genes related to NKactivating pathways and susceptibility to apoptosis compared with ET. Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART.

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The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children

Cited by 24 publications

References 45 publications

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals

T cell immune discriminants of HIV reservoir size in a pediatric cohort of perinatally infected individuals

The CARMA Study: Early Infant Antiretroviral Therapy—Timing Impacts on Total HIV-1 DNA Quantitation 12 Years Later

Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort)

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