TY - JOUR
T1 - Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants
AU - Noguera-Julian, M.
AU - Cozzi-Lepri, A.
AU - Di Giallonardo, F.
AU - Schuurman, R.
AU - Däumer, M.
AU - Aitken, S.
AU - Ceccherini-Silberstein, F.
AU - D'Arminio Monforte, A.
AU - Geretti, A. M.
AU - Booth, C. L.
AU - Kaiser, R.
AU - Michalik, C.
AU - Jansen, K.
AU - Masquelier, B.
AU - Bellecave, P.
AU - Kouyos, R. D.
AU - Castro, E.
AU - Furrer, H.
AU - Schultze, A.
AU - Günthard, H. F.
AU - Brun-Vezinet, F.
AU - Metzner, K. J.
AU - Paredes, R.
AU - Paredes, Roger
AU - Metzner, Karin J.
AU - Cozzi-Lepri, A.
AU - Schuurman, Rob
AU - Brun-Vezinet, Francoise
AU - Günthard, Huldrych
AU - Ceccherini-Silberstein, Francesca
AU - Kaiser, Rolf
AU - Geretti, A. M.
AU - Brockmeyer, Norbert
AU - Masquelier, Bernard
PY - 2016/2/1
Y1 - 2016/2/1
N2 - © 2015 European Society of Clinical Microbiology and Infectious Diseases. Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor 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 apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, 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 the 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 re-analysis of the parent case control study, the 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 non-nucleoside reverse transcriptase inhibitor ART.
AB - © 2015 European Society of Clinical Microbiology and Infectious Diseases. Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor 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 apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, 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 the 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 re-analysis of the parent case control study, the 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 non-nucleoside reverse transcriptase inhibitor ART.
KW - APOBEC3
KW - Human immunodeficiency virus type 1
KW - Minority variants
KW - NNRTI resistance
KW - Resistance
U2 - 10.1016/j.cmi.2015.10.004
DO - 10.1016/j.cmi.2015.10.004
M3 - Article
VL - 22
SP - 191
EP - 200
JO - Clinical Microbiology and Infection
JF - Clinical Microbiology and Infection
SN - 1198-743X
IS - 2
ER -