SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement

Nirmin Alsahafi, Sai Priya Anand, Luis Castillo-Menendez, Myriam Maude Verly, Halima Medjahed, Jérémie Prévost, Alon Herschhorn, Jonathan Richard, Arne Schön, Bruno Melillo, Ernesto I Freire, Amos B. Smith, Joseph Sodroski, Andrés Finzia

Research output: Contribution to journalArticle

Abstract

The entry of human immunodeficiency virus into host cells is mediated by the envelope glycoprotein (Env) trimeric spike, which consists of three exterior gp120 subunits and three transmembrane gp41 subunits. The trimeric Env undergoes extensive conformational rearrangement upon interaction with the CD4 receptor, transitioning from the unliganded, “closed” State 1 to more-open downstream State 2 and State 3 conformations. Changes in “restraining” amino acid residues, such as leucine 193 and isoleucine 423, destabilize State 1 Env, which then assumes entry-competent, downstream conformations. The introduction of an artificial disulfide bond linking the gp120 and gp41 subunits (SOS) in combination with the I559P (IP) change has allowed structural characterization of soluble gp140 (sgp140) trimers. The conformation of these SOSIP-stabilized sgp140 trimers has been suggested to represent the closed native State 1 conformation. Here we compare the impact on the membrane Env conformation of the SOSIP changes with that of the well-characterized changes (L193R and I423A) that shift Env to downstream States 2 and 3. The results presented here suggest that the SOSIP changes stabilize Env in a conformation that differs from State 1 but also from the downstream Env conformations stabilized by L193R or I423A. IMPORTANCE The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer is triggered by receptor binding to mediate the entry of the virus into cells. Most structural studies of Env trimers have utilized truncated soluble gp140 Envs stabilized with the I559P and SOS changes. Here we present evidence indicating that these stabilizing changes have a profound impact on the conformation of Env, moving Env away from the native pretriggered Env conformation. Our studies underscore the need to acquire structural information on the pretriggered Env conformation, which is recognized by most broadly reactive neutralizing antibodies.

Original languageEnglish (US)
Article numbere01080
JournalJournal of Virology
Volume92
Issue number19
DOIs
StatePublished - Oct 1 2018

Fingerprint

Human immunodeficiency virus 1
env Gene Products
HIV-1
glycoproteins
Glycoproteins
receptors
disulfide bonds
Human immunodeficiency virus
isoleucine
neutralizing antibodies
leucine
Virus Internalization
CD4 Antigens
Isoleucine
cells
Neutralizing Antibodies
Leucine
Disulfides
viruses
amino acids

Keywords

  • Env
  • Env conformation
  • HIV-1
  • SOSIP
  • State 1
  • States 2/3

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Alsahafi, N., Anand, S. P., Castillo-Menendez, L., Verly, M. M., Medjahed, H., Prévost, J., ... Finzia, A. (2018). SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement. Journal of Virology, 92(19), [e01080]. https://doi.org/10.1128/JVI.01080-18

SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement. / Alsahafi, Nirmin; Anand, Sai Priya; Castillo-Menendez, Luis; Verly, Myriam Maude; Medjahed, Halima; Prévost, Jérémie; Herschhorn, Alon; Richard, Jonathan; Schön, Arne; Melillo, Bruno; Freire, Ernesto I; Smith, Amos B.; Sodroski, Joseph; Finzia, Andrés.

In: Journal of Virology, Vol. 92, No. 19, e01080, 01.10.2018.

Research output: Contribution to journalArticle

Alsahafi, N, Anand, SP, Castillo-Menendez, L, Verly, MM, Medjahed, H, Prévost, J, Herschhorn, A, Richard, J, Schön, A, Melillo, B, Freire, EI, Smith, AB, Sodroski, J & Finzia, A 2018, 'SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement', Journal of Virology, vol. 92, no. 19, e01080. https://doi.org/10.1128/JVI.01080-18
Alsahafi N, Anand SP, Castillo-Menendez L, Verly MM, Medjahed H, Prévost J et al. SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement. Journal of Virology. 2018 Oct 1;92(19). e01080. https://doi.org/10.1128/JVI.01080-18
Alsahafi, Nirmin ; Anand, Sai Priya ; Castillo-Menendez, Luis ; Verly, Myriam Maude ; Medjahed, Halima ; Prévost, Jérémie ; Herschhorn, Alon ; Richard, Jonathan ; Schön, Arne ; Melillo, Bruno ; Freire, Ernesto I ; Smith, Amos B. ; Sodroski, Joseph ; Finzia, Andrés. / SOSIP changes affect human immunodeficiency virus type 1 envelope glycoprotein conformation and CD4 engagement. In: Journal of Virology. 2018 ; Vol. 92, No. 19.
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AU - Medjahed, Halima

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AU - Herschhorn, Alon

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AU - Schön, Arne

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