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Journal of Virology, May 1999, p. 4360-4371, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cyanovirin-N Binds to gp120 To Interfere with CD4-Dependent Human Immunodeficiency Virus Type 1 Virion Binding, Fusion, and Infectivity but Does Not Affect the CD4 Binding Site on gp120 or Soluble CD4-Induced Conformational Changes in gp120dagger

Mark T. Esser,1 Toshiyuki Mori,2 Isabelle Mondor,3 Quentin J. Sattentau,3,Dagger Barna Dey,4 Edward A. Berger,4 Michael R. Boyd,2 and Jeffrey D. Lifson1,*

Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC-Frederick,1 and Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick Cancer Research and Development Center,2 Frederick, Maryland 21702; Centre d'Immunologie de Marseille-Luminy, Marseille, France3; and Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-04454

Received 23 October 1998/Accepted 10 February 1999

Cyanovirin-N (CV-N), an 11-kDa protein isolated from the cyanobacterium Nostoc ellipsosporum, potently inactivates diverse strains of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus. While it has been well established that the viral surface envelope glycoprotein gp120 is a molecular target of CV-N, the detailed mechanism of action is of further interest. We compared matched native and CV-N-treated virus preparations in a panel of assays that measure viral replication, assessing successive stages of the viral life cycle. CV-N-treated virions failed to infect cells as detected by p24 production and quantitative PCR for HIV-1 reverse transcription products, whereas treatment of the target cells did not block infection, confirming that CV-N acts at the level of the virus, not the target cell, to abort the initial infection process. Compared to native HIV-1 preparations, CV-N-treated HIV-1 virions showed impaired CD4-dependent binding to CD4+ T cells and did not mediate "fusion from without" of CD4+ target cells. CV-N also blocked HIV envelope glycoprotein Env-induced, CD4-dependent cell-cell fusion. Mapping studies with monoclonal antibodies (MAbs) to defined epitopes on the HIV-1 envelope glycoprotein indicated that CV-N binds to gp120 in a manner that does not occlude or alter the CD4 binding site or V3 loop or other domains on gp120 recognized by defined MAbs and does not interfere with soluble CD4-induced conformational changes in gp120. Binding of CV-N to soluble gp120 or virions inhibited subsequent binding of the unique neutralizing MAb 2G12, which recognizes a glycosylation-dependent epitope. However, prior binding of 2G12 MAb to gp120 did not block subsequent binding by CV-N. These results help clarify the mechanism of action of CV-N and suggest that the compound may act in part by preventing essential interactions between the envelope glycoprotein and target cell receptors. This proposed mechanism is consistent with the extensive activity profile of CV-N against numerous isolates of HIV-1 and other lentiviruses and supports the potential broad utility of this protein as a microbicide to prevent the sexual transmission of HIV.

* Corresponding author. Mailing address: Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Building 535, Fifth Floor, Frederick, MD 21702. Phone: (301) 846-5019. Fax: (301) 846-5588. E-mail: lifson{at}avpaxp1.ncifcrf.gov.

dagger Paper 54 in the NCI Laboratory of Drug Discovery Research and Development series HIV-Inhibitory Natural Products (reference 33 is paper 53).

Dagger Present address: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England.

Journal of Virology, May 1999, p. 4360-4371, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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