Cell-to-Cell Transfer of HIV-1 via Virological Synapses Leads to Endosomal Virion Maturation that Activates Viral Membrane Fusion

Abstract

SUMMARY HIV-1 can infect T cells by cell-free virus or by direct virion transfer between cells through cell contact-induced structures called virological synapses (VS). During VS-mediated infection, virions accumulate within target cell endosomes. We show that after crossing the VS, the transferred virus undergoes both maturation and viral membrane fusion. Following VS transfer, viral membrane fusion occurs with delayed kinetics and transferred virions display reduced sensitivity to patient antisera compared to mature, cell-free virus. Furthermore, particle fusion requires that the transferred virions undergo proteolytic maturation within acceptor cell endosomes, which occurs over several hours. Rapid, live cell confocal microscopy demonstrated that viral fusion can occur in compartments that have moved away from the VS. Thus, HIV particle maturation activates viral fusion in target CD4+ T cell endosomes following transfer across the VS and may represent a pathway by which HIV evades antibody neutralization.

HIV Entry and Envelope Glycoprotein-mediated Fusion

“…In an interesting twist, Melikyan and co-workers (62) found that hemifusion occurred at the plasma membrane but that pore expansion occurred following endocytosis in the endosome. Although the endocytic pathway was revealed by observation on the micrometer scale (62,63), it was not supported by examination on the nanoscale in primary lymphocytes (64). Inhibitors of dynaminand clathrin-dependent endocytosis (62,65) have been invoked to argue for HIV entry via endocytosis, but such inhibitors have multifaceted effects on cellular processes, including cell-cell fusion (66).…”

Distinct Requirements for HIV-Cell Fusion and HIV-mediated Cell-Cell Fusion

“…In addition, HIV-1 particles transmitted through virological synapses could, at least temporarily, be attached to both cells across the contact area (88). The fact that cell-to-cell transmission does not normally lead to cell fusion suggests negative regulation of this entry pathway, perhaps through delayed virus maturation (89) or through host factors interfering with the fusion process (90,91). If complete HIV-1 fusion at the cell surface relies on actin, what drives pore dilation in endosomes following CD4-and coreceptor-mediated uptake?…”

Transmission intercellulaire de HTLV-1

“…De même, on ne connaît pas les mécanismes précis d'entrée du virus HTLV-1 dans la cellule cible lors de la transmission synaptique, ou lors du transfert de biofilm. Y a-t-il fusion à la membrane, ou, comme dans le cas du VIH-1, endocytose des particules virales et fusion dans les endosomes [45] ? Enfin, la nécessité d'un contact étroit entre une cellule infectée et sa cible suggère que le succès de l'infection pourrait aussi dépendre de signaux complémentaires induits par l'engagement de protéines cellulaires au moment du contact.…”