Contribution of APOBEC3G/F Activity to the Development of Low-Abundance Drug-Resistant HIV-1 variants.

Noguera-Julian, Marc; Cozzi-Lepri, Alessandro; Di Giallonardo, Francesca; Schuurman, Rob; Däumer, Martin; Aitken, Sue; Ceccherini-Silberstein, Francesca; D'Arminio Monforte, Antonella; Geretti, Anna Maria; Booth, Claire L; Kaiser, Rolf; Michalik, Claudia; Jansen, Klaus; Masquelier, Bernard; Bellecave, Pantxika; Kouyos, Roger D; Castro, Erika; Furrer, Hansjakob; Schultze, Anna; Günthard, Huldrych F; ... (2016). Contribution of APOBEC3G/F Activity to the Development of Low-Abundance Drug-Resistant HIV-1 variants. Clinical microbiology and infection, 22(2), pp. 191-200. Blackwell Publishing 10.1016/j.cmi.2015.10.004

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Plasma drug-resistant minority HIV-1 variants (DRMV) increase the risk of virological failure to first-line NNRTI antiretroviral therapy (ART). The origin of DRMVs in ART-naive patients, however, remains unclear. In a large pan-European case-control study investigating the clinical relevance of pre-existing DRMVs using 454 pyrosequencing, the six most prevalent plasma DRMVs detected corresponded to G-to-A nucleotide mutations (V90I, V106I, V108I, E138K, M184I and M230I). Here, we evaluated if such DRMVs could have emerged from APOBEC3G/F activity. Out of 236 ART-naïve evaluated subjects, APOBEC3G/F hypermutation signatures were detected in plasma viruses of 14 (5.9%) individuals. Samples with minority E138K, M184I, and M230I mutations, but not those with V90I, V106I, or V108I were significantly associated with APOBEC3G/F activity (Fisher's p<0.005), defined as presence of >0.5% of sample sequences with an APOBEC3G/F signature. Mutations E138K, M184I and M230I co-occurred in the same sequence as APOBEC3G/F signatures in 3/9 (33%), 5/11 (45%) and 4/8 (50%) of samples, respectively; such linkage was not found for V90I, V106I or V108I. In-frame STOP codons were observed in 1.5% of all clonal sequences; 14.8% of them co-occurred with APOBEC3G/F signatures. APOBEC3G/F-associated E138K, M184I and M230I appeared within clonal sequences containing in-frame STOP codons in 2/3 (66%), 5/5 (100%) and 4/4 (100%) of the samples. In a reanalysis of the parent case-control study, presence of APOBEC3G/F signatures was not associated with virological failure. In conclusion, the contribution of APOBEC3G/F editing to the development of DRMVs is very limited and does not affect the efficacy of NNRTI ART.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

UniBE Contributor:

Furrer, Hansjakob

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1198-743X

Publisher:

Blackwell Publishing

Language:

English

Submitter:

Annelies Luginbühl

Date Deposited:

19 Nov 2015 10:15

Last Modified:

13 Feb 2016 01:30

Publisher DOI:

10.1016/j.cmi.2015.10.004

PubMed ID:

26482266

Uncontrolled Keywords:

APOBEC3; HIV-1; minority variants; resistance

URI:

https://boris.unibe.ch/id/eprint/72569

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