Accumulated mutations by 6 months of infection collectively render transmitted/founder HIV-1 significantly less fit - 05/02/20

Doi : 10.1016/j.jinf.2019.12.001

Chu Wang ^a,^b,^{^{1
These two authors contributed equally to this work.}}, Donglai Liu ^a,^b,^c,^{^{1
These two authors contributed equally to this work.}}, Tao Zuo ^a,^b, Bhavna Hora ^b, Fangping Cai ^b, Haitao Ding ^d, John Kappes ^d, Christina Ochsenbauer ^d, Wei Kong ^a, Xianghui Yu ^a, Tanmoy Bhattacharya ^e, Alan S Perelson ^e, Feng Gao ^a,^b,^⁎
^a National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun 130012, Jilin, China
^b Department of Medicine and Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
^c Division of the Second in Vitro Diagnostic, National Institute for Food and Drug Control, Beijing 100050, China
^d Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
^e Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA

^⁎Corresponding author at: Department of Medicine, Duke University Medical Center, 244 Sands Building, 303 Research Drive, DUMC 102359, Durham, NC 27710, USA.Department of MedicineDuke University Medical Center244 Sands Building, 303 Research Drive, DUMC 102359DurhamNC27710United States

Highlights

•	Mutations in early HIV-1-infection collectively impair fitness of the T/F viruses.
•	Fitness loss is associated with reduced viral loads from viremia peak.
•	Testing mutations in the cognate T/F genome accurately determinates HIV-1 fitness.

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Summary

Objective

Viral fitness plays an important role in HIV-1 evolution, transmission and pathogenesis. However, how mutations accumulated during early infection affect viral fitness has not been well studied.

Methods

Paired infectious molecular clones (IMCs) for transmitted/founder (T/F) and 6-month (6-mo) viruses post infection were generated from 10 infected individuals to investigate the impact of accumulated mutations on viral fitness by comparing 6-mo viruses to their cognate T/F viruses.

Results

All ten 6-mo viruses were less fit than their cognate T/F viruses. Moreover, the fitness losses of the 6-mo viruses correlated with the decrease in viral loads from the peak of viremia.

Conclusion

These results show that the mutations accumulated during half a year post infection collectively reduce viral fitness and thereby contribute to lowering viral loads.

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Keywords : HIV-1, Mutation, Fitness, Transmitted/founder virus, Infection

Plan

Introduction

Materials and methods

Human subjects

Amplification of viral genome by SGA

Sequence analysis

Generation of infectious molecular clones

Viral replication kinetics

Parallel allele-specific sequencing (PASS) fitness assay

Quantification and statistical analysis

Results

T/F and 6-mo viruses from the same individuals are replication-competent

6-mo viruses are less fit than their cognate T/F viruses

Viral fitness losses are associated with low viral loads

Discussion

Funding

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Vol 80 - N° 2

P. 210-218 - février 2020 Retour au numéro

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Accumulated mutations by 6 months of infection collectively render transmitted/founder HIV-1 significantly less fit - 05/02/20

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Summary

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Methods

Results

Conclusion

Plan

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