Gärtner, K; Domínguez-Rodríguez, S; Heaney, J; Gkouleli, T; Grant, P; Dorgham, K; Sauce, D; ... EPIICAL consortium; + view all Gärtner, K; Domínguez-Rodríguez, S; Heaney, J; Gkouleli, T; Grant, P; Dorgham, K; Sauce, D; Soulie, C; Busby, EJ; O’Sullivan, DM; Spyer, M; Botha, JC; Muñoz-Fernandez, MA; Tagarro, A; Cotugno, N; Huggett, JF; Klein, N; Palma, P; Rojo Conejo, P; Foster, C; Giaquinto, C; Rossi, P; Persaud, D; De Rossi, A; Marcelin, AG; Nastouli, E; EPIICAL consortium; - view fewer (2024) Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART. Frontiers in Immunology , 15 , Article 1334236. 10.3389/fimmu.2024.1334236.

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Abstract

Introduction: Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population. // Methods: Forty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested. // Results: CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study. // Conclusions: Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation.

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