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

doi:10.1016/j.celrep.2020.107749

Slow Receptor Binding of the Noncytopathic HIV-2_UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity

Cell Rep. 2020 Jun 9;31(10):107749. doi: 10.1016/j.celrep.2020.107749.

Authors

Affiliations

¹ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
² Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
³ Department of Immunology Cancer and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Pharmaconeuroimmunology Training Program, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Division of Basic Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA; Pharmaconeuroimmunology Training Program, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ Department of Immunology Cancer and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215, USA.
⁷ Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: aherschh@umn.edu.

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.

Keywords: HIV envelope glycoproteins; binding kinetics; long-lived activation state; molecular mechanism of HIV entry.

Slow Receptor Binding of the Noncytopathic HIV-2_UC1 Envs Is Balanced by Long-Lived Activation State and Efficient Fusion Activity

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