Related Experiment Video
Updated: Aug 25, 2026
Conformational Evaluation of HIV-1 Trimeric Envelope Glycoproteins Using a Cell-based ELISA Assay
Published on: September 14, 2014
Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry
Navid Madani1, Ana Luisa Perdigoto, Kumar Srinivasan
1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute. Department of Pathology and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the "phenylalanine 43 cavity" and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.
Insights
BMS-806 and compound #155 inhibit human immunodeficiency virus type 1 (HIV-1) entry by blocking gp120 conformational changes. Resistance mutations map to a cavity and channel in gp120, revealing drug binding sites.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Human immunodeficiency virus type 1 (HIV-1) entry into host cells is mediated by the envelope glycoproteins gp120 and gp41.
- CD4 binding to gp120 triggers conformational changes essential for viral entry.
- Novel entry inhibitors are needed to combat HIV-1 infection.
Purpose of the Study:
- To characterize the mechanism of action of BMS-806 and compound #155, novel HIV-1 entry inhibitors.
- To identify HIV-1 envelope glycoprotein mutations conferring resistance to BMS-806 and #155.
- To elucidate the structural basis for BMS-806 and #155 binding to gp120.
Main Methods:
- Testing HIV-1 envelope glycoprotein mutants for resistance to BMS-806 and #155.
- Structural analysis to model the binding of BMS-806 and #155 to gp120.
- Investigating the role of V1/V2 loops and N-linked carbohydrates in drug sensitivity.
Main Results:
- BMS-806 and #155 inhibit HIV-1 entry by blocking CD4-induced conformational changes in gp120.
- Resistance mutations cluster in the Phe-43 cavity and an adjacent water-filled channel in gp120.
- Drug sensitivity is indirectly influenced by V1/V2 loops and N-linked carbohydrates.
- A binding site between gp120 receptor-binding regions and the inner domain is proposed.
Conclusions:
- BMS-806 and #155 bind to a specific site on gp120, likely prior to CD4 binding.
- Structural features of gp120, including the Phe-43 cavity, are critical for drug efficacy.
- Understanding the binding mode provides insights into HIV-1 entry inhibition and drug development.
