TY - JOUR
T1 - Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART
AU - Gärtner, Kathleen
AU - Domínguez-Rodríguez, Sara
AU - Heaney, Judith
AU - Gkouleli, Triantafylia
AU - Grant, Paul
AU - Dorgham, Karim
AU - Sauce, Delphine
AU - Soulie, Cathia
AU - Busby, Eloise J.
AU - O’Sullivan, Denise M.
AU - Spyer, Moira
AU - Botha, Johannes C.
AU - Muñoz-Fernandez, Maria Angeles
AU - Tagarro, Alfredo
AU - Cotugno, Nicola
AU - Huggett, Jim F.
AU - Klein, Nigel
AU - Palma, Paolo
AU - Rojo Conejo, Pablo
AU - Foster, Caroline
AU - Giaquinto, Carlo
AU - Rossi, Paolo
AU - Persaud, Deborah
AU - De Rossi, Anita
AU - Marcelin, Anne Geneviève
AU - Nastouli, Eleni
N1 - Publisher Copyright:
Copyright © 2024 Gärtner, Domínguez-Rodríguez, Heaney, Gkouleli, Grant, Dorgham, Sauce, Soulie, Busby, O’Sullivan, Spyer, Botha, Muñoz-Fernandez, Tagarro, Cotugno, Huggett, Klein, Palma, Rojo Conejo, Foster, Giaquinto, Rossi, Persaud, De Rossi, Marcelin and Nastouli.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - HIV-1
KW - adolescents
KW - cell-associated DNA
KW - cell-associated RNA
KW - cytokines
KW - early treated
KW - suppressed
UR - http://www.scopus.com/inward/record.url?scp=85186567964&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85186567964&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2024.1334236
DO - 10.3389/fimmu.2024.1334236
M3 - Article
C2 - 38444847
AN - SCOPUS:85186567964
SN - 1664-3224
VL - 15
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1334236
ER -