Different infectivity of HIV-1 strains is linked to number of envelope trimers required for entry

HIV-1 enters target cells by virtue of envelope glycoprotein trimers that are incorporated at low density in the viral membrane. How many trimers are required to interact with target cell receptors to mediate virus entry, the HIV entry stoichiometry, still awaits clarification. Here, we provide esti...

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Bibliographic Details
Published in:PLoS pathogens 2015-01, Vol.11 (1), p.e1004595-e1004595
Main Authors: Brandenberg, Oliver F, Magnus, Carsten, Rusert, Peter, Regoes, Roland R, Trkola, Alexandra
Format: Article
Language:English
Subjects:
Biology and Life Sciences
Cells, Cultured
Disease transmission
env Gene Products, Human Immunodeficiency Virus - metabolism
Glycoproteins
HEK293 Cells
HIV
HIV infections
HIV-1 - pathogenicity
HIV-1 - physiology
Host-virus relationships
Human immunodeficiency virus
Humans
Identification and classification
Influenza
Kinetics
Mathematical models
Medical research
Medicine and Health Sciences
Models, Theoretical
Physical Sciences
Physiological aspects
Protein Multimerization
Proteins
Vaccines
Virulence (Microbiology)
Virus Internalization
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Summary:HIV-1 enters target cells by virtue of envelope glycoprotein trimers that are incorporated at low density in the viral membrane. How many trimers are required to interact with target cell receptors to mediate virus entry, the HIV entry stoichiometry, still awaits clarification. Here, we provide estimates of the HIV entry stoichiometry utilizing a combined approach of experimental analyses and mathematical modeling. We demonstrate that divergent HIV strains differ in their stoichiometry of entry and require between 1 to 7 trimers, with most strains depending on 2 to 3 trimers to complete infection. Envelope modifications that perturb trimer structure lead to an increase in the entry stoichiometry, as did naturally occurring antibody or entry inhibitor escape mutations. Highlighting the physiological relevance of our findings, a high entry stoichiometry correlated with low virus infectivity and slow virus entry kinetics. The entry stoichiometry therefore directly influences HIV transmission, as trimer number requirements will dictate the infectivity of virus populations and efficacy of neutralizing antibodies. Thereby our results render consideration of stoichiometric concepts relevant for developing antibody-based vaccines and therapeutics against HIV.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004595