HIV-1 strains belonging to large phylogenetic clusters show accelerated escape from integrase inhibitors in cell culture compared with viral isolates from singleton/small clusters.
J Antimicrob Chemother
; 72(8): 2171-2183, 2017 08 01.
Article
em En
| MEDLINE
| ID: mdl-28472323
ABSTRACT
Objectives:
Viral phylogenetics revealed two patterns of HIV-1 spread among MSM in Quebec. While most HIV-1 strains ( n = 2011) were associated with singleton/small clusters (cluster size 1-4), 30 viral lineages formed large networks (cluster size 20-140), contributing to 42% of diagnoses between 2011 and 2015. Herein, tissue culture selections ascertained if large cluster lineages possessed higher replicative fitness than singleton/small cluster isolates, allowing for viral escape from integrase inhibitors.Methods:
Primary HIV-1 isolates from large 20+ cluster ( n = 11) or singleton/small cluster ( n = 6) networks were passaged in vitro in escalating concentrations of dolutegravir, elvitegravir and lamivudine for 24-36 weeks. Sanger and deep sequencing assessed genotypic changes under selective drug pressure.Results:
Large cluster HIV-1 isolates selected for resistance to dolutegravir, elvitegravir and lamivudine faster than HIV-1 strains forming small clusters. With dolutegravir, large cluster HIV-1 variants acquired solitary R263K ( n = 7), S153Y ( n = 1) or H51Y ( n = 1) mutations as the dominant quasi-species within 8-12 weeks as compared with small cluster lineages where R263K ( n = 1/6), S153Y (1/6) or WT species (4/6) were observed after 24 weeks. Interestingly, dolutegravir-associated mutations compromised viral replicative fitness, precluding escalations in concentrations beyond 5-10 nM. With elvitegravir, large cluster variants more rapidly acquired first mutations (T66I, A92G, N155H or S147G) by week 8 followed by sequential accumulation of multiple mutations leading to viral escape (>10 µM) by week 24.Conclusions:
Further studies are needed to understand virological features of large cluster viruses that may favour their transmissibility, replicative competence and potential to escape selective antiretroviral drug pressure.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Seleção Genética
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Infecções por HIV
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HIV-1
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Inibidores de Integrase de HIV
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Farmacorresistência Viral
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Genótipo
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Mutação
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article