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CD4-IgG binding threshold for inactivation of human immunodeficiency virus type 1
I Berkower1, H Mostowski, T E Bull
1Laboratories of Immunoregulation, Food and Drug Administration, National Institutes of Health, Bethesda, Maryland, USA.
Insights
Soluble receptor CD4-IgG hybrid dimers (CD4-IgG) effectively inactivate human immunodeficiency virus type 1 (HIV-1). Even minimal CD4-IgG binding triggers a threshold for complete virus inactivation, demonstrating high efficacy.
Area of Science:
- Virology
- Immunology
- Biochemistry
Background:
- Human immunodeficiency virus type 1 (HIV-1) remains a significant global health challenge.
- Soluble receptor CD4-IgG hybrid dimers (CD4-IgG) are engineered proteins designed to target and neutralize HIV-1.
- Understanding the precise mechanism and stoichiometry of CD4-IgG mediated HIV-1 inactivation is crucial for therapeutic development.
Purpose of the Study:
- To investigate the stoichiometry of HIV-1 inactivation by CD4-IgG.
- To determine the binding threshold of CD4-IgG required for significant virus inactivation.
- To elucidate the relationship between CD4-IgG binding levels and HIV-1 infectivity.
Main Methods:
- HIV-1 inactivation was quantified using a sensitive plaque-forming assay.
- CD4-IgG binding to infected cells was measured via immunofluorescence.
- Virus survival curves were analyzed against varying CD4-IgG binding levels.
Main Results:
- Ninety percent HIV-1 inactivation was observed at 10% of saturating CD4-IgG binding levels.
- At 1.4% of maximum binding, 44% of the virus remained infectious.
- A threshold model demonstrated that viruses binding above a specific CD4-IgG level were completely inactivated.
Conclusions:
- CD4-IgG binding to as little as 1.4% of gp120 sites initiates the inactivation threshold.
- As few as 3 CD4-IgG molecules binding per virion can trigger inactivation.
- These findings highlight the high efficiency and potent antiviral activity of CD4-IgG against HIV-1.
Abstract:
The stoichiometry of human immunodeficiency virus type 1 (HIV-1) inactivation by soluble receptor CD4-IgG hybrid dimers (CD4-IgG) was examined. The extent of HIV-1 inactivation was measured in a sensitive plaque-forming assay, and the corresponding level of CD4-IgG binding was determined by immunofluorescence of infected cells. Ninety percent virus inactivation occurred at relatively low levels of CD4-IgG binding (10% of the saturating level). At even lower binding levels (1.4% of maximum binding), virus survival was 44%. Over a broad range of binding conditions, the survival curve followed a model in which viruses binding more than a threshold level of CD4-IgG were completely inactivated, while viruses binding less remained infectious. The data indicate that CD4-IgG binding to 1.4% of gp120 binding sites equals the threshold for inactivation. Thus, virus inactivation can begin when 3 CD4-IgG (of approximately 216 gp120 sites) bind per virion.