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Impact of suboptimal APOBEC3G neutralization on the emergence of HIV drug resistance in humanized mice


Hernandez, Matthew M; Fahrny, Audrey; Jayaprakash, Anitha; Gers-Huber, Gustavo; Dillon-White, Marsha; Audigé, Annette; Mulder, Lubbertus C F; Sachidanandam, Ravi; Speck, Roberto F; Simon, Viviana (2019). Impact of suboptimal APOBEC3G neutralization on the emergence of HIV drug resistance in humanized mice. Journal of Virology, 94(5):0.

Abstract

HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, HIV-ΔSLQ) that differ in their ability to counteract APOBEC3G (A3G). Infected mice remained naïve or were treated with the RT inhibitor lamivudine (3TC). Viremia, emergence of drug resistant variants and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time HIV-45G replication was significantly reduced compared to HIV-WT in the absence of 3TC treatment. In contrast, treatment response differed significantly between HIV-45G and HIV-WT infected mice. Antiretroviral treatment failed in 91% of HIV-45G infected mice while only 36% of HIV-WT infected mice displayed a similar negative outcome. Emergence of 3TC resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase (RT) and 6,985 vif sequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all animals. Upon treatment, the composition of the plasma quasispecies rapidly changed leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G but not in HIV-WT infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but display a fitness advantage in the presence of antiretroviral treatment.IMPORTANCE Both viral (e.g., reverse transcriptase, RT) and host factors (e.g., APOBEC3G (A3G)) can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment of humanized mice.

Abstract

HIV diversification facilitates immune escape and complicates antiretroviral therapy. In this study, we take advantage of a humanized mouse model to probe the contribution of APOBEC3 mutagenesis to viral evolution. Humanized mice were infected with isogenic HIV molecular clones (HIV-WT, HIV-45G, HIV-ΔSLQ) that differ in their ability to counteract APOBEC3G (A3G). Infected mice remained naïve or were treated with the RT inhibitor lamivudine (3TC). Viremia, emergence of drug resistant variants and quasispecies diversification in the plasma compartment were determined throughout infection. While both HIV-WT and HIV-45G achieved robust infection, over time HIV-45G replication was significantly reduced compared to HIV-WT in the absence of 3TC treatment. In contrast, treatment response differed significantly between HIV-45G and HIV-WT infected mice. Antiretroviral treatment failed in 91% of HIV-45G infected mice while only 36% of HIV-WT infected mice displayed a similar negative outcome. Emergence of 3TC resistant variants and nucleotide diversity were determined by analyzing 155,462 single HIV reverse transcriptase (RT) and 6,985 vif sequences from 33 mice. Prior to treatment, variants with genotypic 3TC resistance (RT-M184I/V) were detected at low levels in over a third of all animals. Upon treatment, the composition of the plasma quasispecies rapidly changed leading to a majority of circulating viral variants encoding RT-184I. Interestingly, increased viral diversity prior to treatment initiation correlated with higher plasma viremia in HIV-45G but not in HIV-WT infected animals. Taken together, HIV variants with suboptimal anti-A3G activity were attenuated in the absence of selection but display a fitness advantage in the presence of antiretroviral treatment.IMPORTANCE Both viral (e.g., reverse transcriptase, RT) and host factors (e.g., APOBEC3G (A3G)) can contribute to HIV sequence diversity. This study shows that suboptimal anti-A3G activity shapes viral fitness and drives viral evolution in the plasma compartment of humanized mice.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Microbiology
Life Sciences > Immunology
Life Sciences > Insect Science
Life Sciences > Virology
Language:English
Date:4 December 2019
Deposited On:13 Jan 2020 09:40
Last Modified:29 Jul 2020 12:23
Publisher:American Society for Microbiology
ISSN:0022-538X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/JVI.01543-19
PubMed ID:31801862

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