Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state

Hillel Haim; Zhihai Si; Navid Madani; Liping Wang; Joel R Courter; Amy Princiotto; Aemro Kassa; Marciella DeGrace; Kathleen McGee-Estrada; Megan Mefford; Dana Gabuzda; Amos B Smith III; Joseph Sodroski

doi:10.1371/journal.ppat.1000360

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Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state

Journal article

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Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state

Hillel Haim, Zhihai Si, Navid Madani, Liping Wang, Joel R Courter, Amy Princiotto, Aemro Kassa, Marciella DeGrace, Kathleen McGee-Estrada, Megan Mefford, …

PLoS pathogens, Vol.5(4), pp.e1000360-e1000360

04/2009

DOI: 10.1371/journal.ppat.1000360

PMCID: PMC2655723

PMID: 19343205

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Abstract

Binding to the CD4 receptor induces conformational changes in the human immunodeficiency virus (HIV-1) gp120 exterior envelope glycoprotein. These changes allow gp120 to bind the coreceptor, either CCR5 or CXCR4, and prime the gp41 transmembrane envelope glycoprotein to mediate virus-cell membrane fusion and virus entry. Soluble forms of CD4 (sCD4) and small-molecule CD4 mimics (here exemplified by JRC-II-191) also induce these conformational changes in the HIV-1 envelope glycoproteins, but typically inhibit HIV-1 entry into CD4-expressing cells. To investigate the mechanism of inhibition, we monitored at high temporal resolution inhibitor-induced changes in the conformation and functional competence of the HIV-1 envelope glycoproteins that immediately follow engagement of the soluble CD4 mimics. Both sCD4 and JRC-II-191 efficiently activated the envelope glycoproteins to mediate infection of cells lacking CD4, in a manner dependent on coreceptor affinity and density. This activated state, however, was transient and was followed by spontaneous and apparently irreversible changes of conformation and by loss of functional competence. The longevity of the activated intermediate depended on temperature and the particular HIV-1 strain, but was indistinguishable for sCD4 and JRC-II-191; by contrast, the activated intermediate induced by cell-surface CD4 was relatively long-lived. The inactivating effects of these activation-based inhibitors predominantly affected cell-free virus, whereas virus that was prebound to the target cell surface was mainly activated, infecting the cells even at high concentrations of the CD4 analogue. These results demonstrate the ability of soluble CD4 mimics to inactivate HIV-1 by prematurely triggering active but transient intermediate states of the envelope glycoproteins. This novel strategy for inhibition may be generally applicable to high-potential-energy viral entry machines that are normally activated by receptor binding.

Animals

CD4 Antigens - metabolism

CD4 Antigens - pharmacology

Cell Line

Cercopithecus aethiops

COS Cells

HIV Envelope Protein gp120 - chemistry

HIV Envelope Protein gp120 - metabolism

HIV Envelope Protein gp41 - chemistry

HIV Envelope Protein gp41 - metabolism

HIV-1 - drug effects

HIV-1 - physiology

Humans

Molecular Mimicry

Protein Binding

Protein Conformation - drug effects

Recombinant Proteins - metabolism

Recombinant Proteins - pharmacology

Temperature

Virus Attachment

Virus Internalization - drug effects

Details

Title: Subtitle: Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state
Creators: Hillel Haim
Zhihai Si
Navid Madani
Liping Wang
Joel R Courter
Amy Princiotto
Aemro Kassa
Marciella DeGrace
Kathleen McGee-Estrada
Megan Mefford
Dana Gabuzda
Amos B Smith III
Joseph Sodroski
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.5(4), pp.e1000360-e1000360
DOI: 10.1371/journal.ppat.1000360
PMID: 19343205
PMCID: PMC2655723
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Grant note: U19 AI067854 / NIAID NIH HHS GM56550 / NIGMS NIH HHS R37 AI024755 / NIAID NIH HHS R01 MH083588-11 / NIMH NIH HHS R01 MH083588-10A2 / NIMH NIH HHS P01 GM056550 / NIGMS NIH HHS R01 MH083588 / NIMH NIH HHS AI24755 / NIAID NIH HHS U01 AI067854 / NIAID NIH HHS AI67854 / NIAID NIH HHS R01 MH083588-12 / NIMH NIH HHS
Language: English
Date published: 04/2009
Academic Unit: Microbiology and Immunology
Record Identifier: 9984208754402771

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