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Estimating the stoichiometry of HIV entry


Magnus, C; Rusert, P; Bonhoeffer, S; Trkola, A; Regoes, R R (2009). Estimating the stoichiometry of HIV entry. Journal of Virology, 83(3):1523-1531.

Abstract

To enter its target cells, HIV first attaches to the cells and fuses with the cell membrane. The attachment and fusion involves envelope glycoprotein trimers on the surface of the virion, and the CD4 receptor and chemokine co-receptors on the surface of the target cell. The stoichiometry of entry, that is the number of bonds between such trimers and CD4 that are required for infection, is unknown. Pseudotyped virions that express mixed trimers consisting of functional and non-functional envelope proteins have been used to study how many trimer-receptor interactions are required for virus entry. However, to extract information on the stoichiometry of entry from data generated in in vitro infectivity assays with such viruses, mathematical models are required. Here, we develop mathematical models that can be used to infer the stoichiometry of entry. Fitting our simplest model to previously published data by Yang et al. (18), we estimate that the number of trimer-receptor interactions required for HIV to infect a target cell is approximately 8, which is higher than previous estimates. We also consider model extensions that explain some systematic deviations of the data from the prediction of the simplest model. However, these extended models yield very different estimates of the stoichiometry of entry ranging from 2-19. These results strongly suggest that, based on our present knowledge of HIV entry, the stoichiometry of this process cannot be reliably estimated. Our study identifies parameters that need to be defined to render the estimation of the stoichiometry of entry possible.

Abstract

To enter its target cells, HIV first attaches to the cells and fuses with the cell membrane. The attachment and fusion involves envelope glycoprotein trimers on the surface of the virion, and the CD4 receptor and chemokine co-receptors on the surface of the target cell. The stoichiometry of entry, that is the number of bonds between such trimers and CD4 that are required for infection, is unknown. Pseudotyped virions that express mixed trimers consisting of functional and non-functional envelope proteins have been used to study how many trimer-receptor interactions are required for virus entry. However, to extract information on the stoichiometry of entry from data generated in in vitro infectivity assays with such viruses, mathematical models are required. Here, we develop mathematical models that can be used to infer the stoichiometry of entry. Fitting our simplest model to previously published data by Yang et al. (18), we estimate that the number of trimer-receptor interactions required for HIV to infect a target cell is approximately 8, which is higher than previous estimates. We also consider model extensions that explain some systematic deviations of the data from the prediction of the simplest model. However, these extended models yield very different estimates of the stoichiometry of entry ranging from 2-19. These results strongly suggest that, based on our present knowledge of HIV entry, the stoichiometry of this process cannot be reliably estimated. Our study identifies parameters that need to be defined to render the estimation of the stoichiometry of entry possible.

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57 citations in Web of Science®
60 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 2009
Deposited On:22 Dec 2008 10:01
Last Modified:05 Apr 2016 12:42
Publisher:American Society for Microbiology
ISSN:0022-538X
Additional Information:Copyright: American Society for Microbiology
Publisher DOI:https://doi.org/10.1128/JVI.01764-08
PubMed ID:19019953

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