title: Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.
abstract: A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Beauparlant
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Rusert
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Magnus
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Claus
authors.identifier: 0000-0002-5712-8529
authors.initials: C
authors.lastname: Kadelka
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Weber
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Therese
authors.initials: T
authors.lastname: Uhr
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Osvaldo
authors.identifier: 0000-0002-9082-8607
authors.initials: O
authors.lastname: Zagordi
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Corinna
authors.identifier: 0000-0001-5784-6048
authors.initials: C
authors.lastname: Oberle
authors.affiliation: Program in Molecular Medicine, Biotech II, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Maria J
authors.identifier: 0000-0003-2020-6471
authors.initials: MJ
authors.lastname: Duenas-Decamp
authors.affiliation: Program in Molecular Medicine, Biotech II, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Metzner
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.identifier: 0000-0002-1142-6723
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Alexandra
authors.identifier: 0000-0003-1013-876X
authors.initials: A
authors.lastname: Trkola
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D015704:CD4 Antigens / Q000378:metabolism*; D002469:Cell Separation; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008264:Macrophages / Q000821:virology; D056189:Viral Tropism / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120