Slow Receptor Binding of the Noncytopathic HIV-2UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity

Miranda Harris, Sneha Ratnapriya, Angela Chov, Héctor Cervera, Alisha Block, Christopher Gu, Nathaniel Talledge, Louis M. Mansky, Joseph Sodroski, Alon Herschhorn

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Many HIV strains downregulate the levels of CD4 receptor on the surface of infected cells to prevent superinfection. In contrast, the rare HIV-2 UC1 strain is noncytopathic and has no effect on CD4 expression in infected cells but still replicates as efficiently as more cytopathic strains in peripheral blood mononuclear cells (PBMCs). Here, we show that HIV-2 UC1 Env interactions with the CD4 receptor exhibit slow association kinetics, whereas the dissociation kinetics is within the range of cytopathic strains. Despite the resulting 10- to 100-fold decrease in binding affinity, HIV-2 UC1 Envs exhibit long-lived activation state and efficient fusion activity. These observations suggest that HIV-2 UC1 Envs evolved to balance low affinity with an improved and readily triggerable molecular machinery to mediate entry. Resistance to cold exposure, similar to many primary HIV-1 isolates, and to sCD4 neutralization suggests that HIV-2 UC1 Envs preferentially sample a closed Env conformation. Our data provide insights into the mechanism of HIV entry.

Original languageEnglish (US)
Article number107749
JournalCell reports
Volume31
Issue number10
DOIs
StatePublished - Jun 9 2020

Bibliographical note

Funding Information:
We thank Eva Perez-Greene for helping to prepare the revised manuscript, as well as Paula Cannon and Nick Llewellyn for providing the HIV-2 ROD10 and HIV-2 ROD14 Env-expressing plasmids. A.H. is the recipient of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research ( 108501-53-RKNT ) and a phase II amfAR research grant ( 109285-58-RKVA ) for independent investigators. This work was supported by internal funds of the Department of Medicine at the University of Minnesota and by NIH/NIDA grant 1DP2DA049279-01 (to A.H.). N.T. was supported by NIH F32 DA007097 , and L.M.M. was supported by NIH R01 AI150468 . Molecular graphics and analyses were performed with UCSF Chimera, which is supported by NIH P41-GM103311 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • HIV envelope glycoproteins
  • binding kinetics
  • long-lived activation state
  • molecular mechanism of HIV entry

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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