Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence

Avettand-Fènoël, Véronique; Lechenadec, Jérome; Diallo, Mamadou H.; Fillion, Martin; Mélard, Adeline; Samri, Assia; Dollfus, Catherine; Blanche, Stéphane; Faye, Albert; Amokrane, Kahina; Autran, Brigitte; Buseyne, Florence; Warszawski, Josiane; Frange, Pierre; Study, Anrs-Ep Cleac

doi:10.1093/cid/ciaa1931

Cited by 4 publications

(5 citation statements)

References 34 publications

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“…As expected, no association was observed between HIV reservoir and the time to any ART, including monotherapy in early years (p=0.443 for tDNA and ρ =-0.079; p=0.8567 for uDNA). These findings suggest that shades of delay in ART initiation in this cohort associate with tDNA levels and are in line with previous reports in PHIV ( 50 , 51 ). Interestingly, however, there was no relationship between uDNA levels and time to ART, suggesting that factors other than ART influence presence/absence of uDNA.…”

Section: Resultssupporting

confidence: 93%

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

et al. 2022

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The quantification of proviral DNA is raising interest in view of clinical management and functional HIV eradication. Measures of all unintegrated HIV DNA (uDNA) forms in infected reservoir cells provides information on recent replication events that is not found from other proviral DNA assays. To evaluate its actual relevance in a cohort of perinatally-infected adult HIV patients (PHIV), we studied how peripheral blood mononuclear cell uDNA levels correlated with total HIV DNA (tDNA) and with overall replication or innate immune control parameters including NK cell activation/exhaustion and lymphoid turnover. Twenty-two PHIV were included, with successfully controlled HIV (HIV RNA <50 copies/mL) on combined antiretroviral therapy for mean of 8.7 ± 3.9 years. uDNA accounted for 16 [5.2-83.5] copies/µg and was strongly correlated with tDNA (ρ=0.700, p=0.001). Flow cytometric analysis of peripheral NK cells showed that CD69 expression was directly correlated uDNA (p=0.0412), but not with tDNA. Interestingly, CD56-CD16+NK cells which include newly described inflammatory precursors and terminally differentiated cells were directly correlated with uDNA levels (p<0.001), but not with tDNA, and an inverse association was observed between the proportion of NKG2D+ NK cells and uDNA (ρ=-0.548, p=0.015). In addition, CD34+DNAM-1brightCXCR4+ inflammatory precursor frequency correlated directly with uDNA levels (ρ=0.579, p=0.0075). The frequencies of CD56-CD16+ and CD34+DNAM-1brightCXCR4+ cells maintained association with uDNA levels in a multivariable analysis (p=0.045 and p=0.168, respectively). Thus, control of HIV-1 reservoir in aviremic patients on ART is an active process associated with continuous NK cell intervention and turnover, even after many years of treatment. Quantification of linear and circular uDNA provides relevant information on the requirement for ongoing innate immune control in addition to ART, on recent replication history and may help stratify patients for functional HIV eradication protocols with targeted options.

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Section: Resultssupporting

confidence: 93%

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

et al. 2022

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“…Regardless of the mode of transmission earlier ART is generally associated with a smaller reservoir during viremia suppression (210,214,(225)(226)(227)(228)(229)(230)(231)(232)(233)(234)(235)(236)(237), although starting ART within 14 days of life may not lead to significantly greater HIV DNA persistence compared to within 48 hours of life (238). ART initiation within 8 days has also been associated with a faster HIV DNA decay compared to ART started at 5 months (239).…”

Section: Implications For Cure Approachesmentioning

confidence: 99%

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

et al. 2021

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Despite the significant progress that has been made to eliminate vertical HIV infection, more than 150,000 children were infected with HIV in 2019, emphasizing the continued need for sustainable HIV treatment strategies and ideally a cure for children. Mother-to-child-transmission (MTCT) remains the most important route of pediatric HIV acquisition and, in absence of prevention measures, transmission rates range from 15% to 45% via three distinct routes: in utero, intrapartum, and in the postnatal period through breastfeeding. The exact mechanisms and biological basis of these different routes of transmission are not yet fully understood. Some infants escape infection despite significant virus exposure, while others do not, suggesting possible maternal or fetal immune protective factors including the presence of HIV-specific antibodies. Here we summarize the unique aspects of HIV MTCT including the immunopathogenesis of the different routes of transmission, and how transmission in the antenatal or postnatal periods may affect early life immune responses and HIV persistence. A more refined understanding of the complex interaction between viral, maternal, and fetal/infant factors may enhance the pursuit of strategies to achieve an HIV cure for pediatric populations.

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“…We found no association between CD4T N and virological history in either children or adolescents. Indeed, E-Ado had the lowest CD4T N , despite having the lowest normalized exposure to HIV RNA > 400 copies/ml (median 9% of their lifetime) and low HIV-DNA levels (16). In HIV-infected adolescents who had no access to early ART, CD4T N and T RTE levels were, paradoxically, higher in those with uncontrolled viremia, and HIV replication was correlated with CD4T N levels (21).…”

Section: Discussionmentioning

confidence: 97%

“…The ANRS-EP59-CLEAC study investigated the immunological and virological characteristics of HIV-1infected children over five years of age and adolescents, as a function of age at ART initiation (< 6 months vs. ≥ 24 months of age). We included participants with an initial period of viral suppression but without any criteria on the persistence of viral control (16). Here, we focused on the proportions of CD4T N and CD8T N , the major indicators of qualitative immune reconstitution (17), and their relationships with current and past HIV disease parameters and current immune activation (3).…”

Section: Introductionmentioning

confidence: 99%

Impact of Early Versus Late Antiretroviral Treatment Initiation on Naive T Lymphocytes in HIV-1-Infected Children and Adolescents – The-ANRS-EP59-CLEAC Study

Frange

Montange²,

Chenadec³

et al. 2021

Front. Immunol.

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BackgroundThe early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8TN), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)).MethodsThe ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models.ResultsAt the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8TN percentages (medians: 48.7% vs. 31.0%, P = 0.001), and a marginally higher CD4TN (61.2% vs. 53.1%, P = 0.33). In adolescents, early ART was associated with low CD4TN percentages and less differentiated memory CD8 T cells. CD4TN and CD8TN levels were inversely related to cellular activation and gut permeability.ConclusionIn children and adolescents, the benefits of early ART for CD8TN were clear after long-term ART. The impact of early ART on CD4TN appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the de novo production of TN cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on TN levels.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02674867.

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Initiating Antiretroviral Treatment Early in Infancy Has Long-term Benefits on the Human Immunodeficiency Virus Reservoir in Late Childhood and Adolescence

Cited by 4 publications

References 34 publications

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

Persistence of Unintegrated HIV DNA Associates With Ongoing NK Cell Activation and CD34+DNAM-1brightCXCR4+ Precursor Turnover in Vertically Infected Patients Despite Successful Antiretroviral Treatment

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

Impact of Early Versus Late Antiretroviral Treatment Initiation on Naive T Lymphocytes in HIV-1-Infected Children and Adolescents – The-ANRS-EP59-CLEAC Study

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