title: Different infectivity of HIV-1 strains is linked to number of envelope trimers required for entry.
abstract: 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.
authors.affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
authors.forename: Oliver F
authors.initials: OF
authors.lastname: Brandenberg
authors.affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Magnus
authors.affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Rusert
authors.affiliation: Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.affiliation: Institute of Medical Virology, University of Zürich, Zürich, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
mesh_terms: D002478:Cells, Cultured; D057809:HEK293 Cells; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008962:Models, Theoretical; D055503:Protein Multimerization; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus