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

Abstract

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.

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

“…Within the AIM+ cells, we measured production of IL-2, IL-21, IFN-γ and TNF-α for CD4 T cells and IL-2, IFN-γ, TNF-α, Perforin, and Granzyme B along with the degranulation marker CD107a for CD8 T cells ( S2E and S2F Fig ). Cell-associated HIV DNA measured in PBMC from the same samples was used as a measurement of HIV reservoir size [ 31 , 33 – 34 ]. HIV DNA was measured in purified CD4 T cells in a subset of participants (n = 31) and strongly correlated with the PBMC results from the full cohort used in this study (n = 34) (p-value <0.0001, r-value = +0.66).…”

“…Due to the importance of the time of treatment initiation on preservation of immune functionality [ 35 – 36 ] and HIV viral reservoir size [ 31 , 37 ], we determined the statistical interaction of the variable TI on the calculated effect for all predictors. Among the predictors identified, all showed positive associations with HIV DNA, except for CD4/CD40L+ and CD4 Effector/CD38-HLA-DR+ which were negatively associated ( Fig 2 ).…”

“…At present, early initiation of ART is the most efficient therapeutic intervention to limit seeding of HIV reservoirs. Infants born to HIV infected mothers offer a unique opportunity for ART initiation within hours of infection making this population prime candidates for testing therapeutic interventions for HIV cure [29][30][31]. However, the majority of studies have been performed in adults and therefore immune correlates of reservoir size and viral control mechanisms in children are lacking.…”

“…HIV cell-associated DNA in total PBMC. Total HIV DNA was quantified from PBMC at the enrollment time point for all patients using an in-house, real-time quantitative PCR assay as previously described [31]. Briefly, total nucleic acid was extracted from PBMCs on the Qiasymphony platform using the DSP virus/pathogen mini kit (Qiagen) according to the manufacturer's protocol.…”

“…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.…”