The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness

Sugrue, E. et al. (2022) The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. PLoS Pathogens, 18(11), e1010973. (doi: 10.1371/journal.ppat.1010973) (PMID:36399512) (PMCID:PMC9718408)

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HIV-1 transmission via sexual exposure is an inefficient process. When transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)-resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ‘antiviral state’, we established a single pair of fluorescent TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening to identify candidate antiviral effectors. However, we observed a relatively uniform ISG resistance of transmitted HIV-1, and this directed us to investigate possible underlying mechanisms. Simple simulations, where we varied a single parameter, illustrated that reduced growth rate could possibly underly apparent interferon sensitivity. To examine this possibility, we closely monitored in vitro propagation of a model TF/CC pair (closely matched in replicative fitness) over a targeted range of IFN concentrations. Fitting standard four-parameter logistic growth models, in which experimental variables were regressed against growth rate and carrying capacity, to our in vitro growth curves, further highlighted that small differences in replicative growth rates could recapitulate our in vitro observations. We reasoned that if growth rate underlies apparent interferon resistance, transmitted HIV-1 would be similarly resistant to any growth rate inhibitor. Accordingly, we show that two transmitted founder HIV-1 viruses are relatively resistant to antiretroviral drugs, while their matched chronic control viruses were more sensitive. We propose that, when present, the apparent IFN resistance of transmitted HIV-1 could possibly be explained by enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences. However, further work is required to establish how generalisable this mechanism of relative IFN resistance might be.

Item Type:Articles
Additional Information:Funding: This study was supported by Medical Research Council ( mrc) awards MR/P022642/1 (SJW and SJR), MC_UU_12014/12 (DLR and JH) and MC_UU_12018/12 (AdSF) alongside Wellcome Trust investment ( 201366/Z/16/Z (to SJR).
Glasgow Author(s) Enlighten ID:Rihn, Dr Suzannah and Truxa, Mr Sven and Robertson, Professor David and Da Silva Filipe, Dr Ana and Vattipally, Dr Sreenu and Wilson, Professor Sam and Wickenhagen, Mr Arthur and Aziz, Muhamad Afiq Bin and Sugrue, Dr Elena and Hughes, Dr Joseph and Mollentze, Dr Nardus and Tong, Dr Lily
Authors: Sugrue, E., Wickenhagen, A., Mollentze, N., Aziz, M. A., Sreenu, V. B., Truxa, S., Tong, L., da Silva Filipe, A., Robertson, D. L., Hughes, J., Rihn, S. J., and Wilson, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN (Online):1553-7374
Published Online:18 November 2022
Copyright Holders:Copyright © 2022 Sugrue et al.
First Published:First published in PLoS Pathogens 18(11): e1010973
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301840Host and Viral Determinants of Interferon Resistance During HIV-1 TransmissionSam WilsonMedical Research Council (MRC)MR/P022642/1III - Centre for Virus Research
172630014Cross-Cutting Programme – Viral Genomics and Bioinformatics (Programme 9)David RobertsonMedical Research Council (MRC)MC_UU_12014/12III - Centre for Virus Research
173514Inhibition of HIV-1 by Type II InterferonSuzannah RihnWellcome Trust (WELLCOTR)201366/Z/16/ZIII - Centre for Virus Research