Proportion of APOBEC3-induced defective HIV DNA after 1 year of dolutegravir + lamivudine simplification in the ANRS 167 LAMIDOL trial
Author:
Mazouz Fella1, Bertine Mélanie1, Coppée Romain1ORCID, Storto Alexandre1, Katlama Christine2, Landman Roland3, Cabié André4, Peytavin Gilles5ORCID, Raffi François6, Yazdanpanah Yazdan3, Descamps Diane1, Joly Véronique3, Ghosn Jade3ORCID, Charpentier Charlotte1, Bouchaud Olivier, Goujard Cécile, Phung Bao, Viard Jean Paul, Weiss Laurence, Duvivier Claudine, Katlama Christine, Girard Pierre Marie, Molina Jean Michel, Morlat Philippe, Jacomet Christine, Piroth Lionel, Cabie André, Poizot-Martin Isabelle, Reynes Jacques, Allavena Clotilde, Billaud Eric, Boutoille David, Raffi François, Reliquet Véronique, Rosenthal Eric, Naqvi Alissa, Aumaitre Hughes, Souala Faouzi, Bernard Louis, Biezunski Noémie, Ajana Faiza, Miailhes Patrick, Amat Karine, Benalicherif Aida, Sylla Babacar,
Affiliation:
1. Service de Virologie, INSERM, IAME, UMR 1137, AP-HP, Hôpital Bichat-Claude Bernard, Université Paris Cité , Paris , France 2. Service de Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, Sorbonne Université , Paris , France 3. Service de Maladies Infectieuses et Tropicales, INSERM, IAME, UMR 1137, AP-HP, Hôpital Bichat-Claude Bernard, Université Paris Cité , Paris , France 4. Service de Maladies Infectieuses et Tropicales, CHU Martinique , Fort-de-France , France 5. Service de Pharmacologie, INSERM, IAME, UMR 1137, AP-HP, Hôpital Bichat-Claude Bernard, Université Paris Cité , Paris , France 6. Service de Maladies Infectieuses et Tropicales, CHU Hôtel-Dieu , Nantes , France
Abstract
Abstract
Background
Hypermutated viruses induced by APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins comprise some of the defective viruses in the HIV reservoir. Here, we assessed the proportion of APOBEC3-induced defective proviruses in HIV-positive patients before and after receiving dolutegravir + lamivudine dual therapy.
Methods
PBMCs of virologically suppressed patients enrolled in the ANRS 167 LAMIDOL trial, evaluating a switch from triple therapy to dolutegravir + lamivudine, were collected 8 weeks before (W-8) and 48 weeks after (W48) dual-therapy initiation. The Vif and RT regions were subject to next-generation sequencing. Bioinformatic algorithms were developed to identify APOBEC3-defective sequences and APOBEC3-related drug resistance mutations (APOMuts). All hypermutated sequences and those containing at least one stop codon were considered as defective.
Results
One hundred and four patients were enrolled (median virological suppression duration: 4.2 years; IQR: 2.0–9.1). Proviral defective reads at W-8 and W48 were detected in Vif in 22% and 29% of patients, respectively, and in RT in 38% and 42% of patients, respectively. At least one APOMut was present in proviruses of 27% and 38% of patients at W-8 and W48, respectively. The ratio of APOMuts/number of potential APOMut sites was significantly higher at W48 (16.5%) than at W-8 (9.8%, P = 0.007). The presence of APOBEC3-defective viruses at W-8 was not associated with HIV total DNA level, nor with the third drug class received prior to switching to dolutegravir + lamivudine, nor with the duration of virological suppression.
Conclusions
Whereas no significant change in the proportion of patients with APOBEC3-defective proviruses was evidenced after 1 year of dolutegravir + lamivudine maintenance, enrichment in APOMuts was observed. Further longer-term studies are needed to assess the other forms of defective viruses with dual-therapy.
Funder
ANRS MIE France REcherche Nord&Sud Sida-hiv Hépatites ViiV Healthcare, which
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)
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