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.
Highlights
To infect cells, HIV-1 virions need to fuse their membrane with the target cell membrane, a process triggered by the viral envelope glycoprotein trimer [1,2]
In the case of HIV, fusion is executed by envelope glycoprotein trimers upon interaction with adequate receptor molecules on the target cell membrane [1,8]
Definition of the components involved in HIV entry and the membrane fusion process is of particular interest as improved understanding of the determinants of HIV entry bears the promise to funnel the development of enhanced strategies to prevent and treat viral infections [1,7]
Summary
HIV-1 virions need to fuse their membrane with the target cell membrane, a process triggered by the viral envelope (env) glycoprotein trimer [1,2]. Due to its key function in the virus life cycle and as prime target for neutralizing antibodies and entry inhibitors, analyses of env trimer structure and function remain in the focus of current HIV vaccine and drug research [3,4,5]. Subsequent co-receptor binding activates the gp transmembrane subunits, which triggers a prototypic class I fusion process via insertion of the N-terminal fusion peptides into the target cell membrane. Refolding of the gp N- and C-terminal heptad repeat regions into six-helix bundles drives approximation and fusion of viral and target cell membranes [1,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
