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Gene Editing of Primary Rhesus Macaque B Cells
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Protection against SIV in Rhesus Macaques Using Albumin and CD4-Based Vector-Mediated Gene Transfer.

Sergei Spitsin1, Bruce C Schnepp1, Mary J Connell1

  • 1Department of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia and Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.

Molecular Therapy. Methods & Clinical Development
|June 2, 2020
PubMed
Summary
This summary is machine-generated.

Recombinant adeno-associated virus (rAAV) vectors delivered novel immunoadhesins for simian immunodeficiency virus (SIV) neutralization. Albumin fusion extended protection but presented challenges, while CD4-based constructs offered broader SIV strain coverage.

Keywords:
CD4 immunoadhesinsHIVImmunodhesinsSIVadeno-associated virusalbuminbroad cross-protectionimmunoprophylaxis

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Area of Science:

  • Immunology
  • Virology
  • Gene Therapy

Background:

  • Simian immunodeficiency virus (SIV) infection in rhesus macaques is a key model for human immunodeficiency virus (HIV) research.
  • Developing effective SIV/HIV therapeutics requires strategies that provide broad neutralization and long-lasting protection.
  • Recombinant adeno-associated virus (rAAV) vectors offer a platform for in vivo gene delivery to produce therapeutic molecules.

Purpose of the Study:

  • To evaluate immunoadhesins, engineered antibody-like molecules, delivered via rAAV for SIV neutralization.
  • To assess the impact of fusing immunoadhesins with albumin to extend their half-life and in vivo longevity.
  • To compare the efficacy of antibody-based versus CD4-based immunoadhesins, and their albumin fusions, against SIV challenge.

Main Methods:

  • Intramuscular injection of rAAV vectors encoding immunoadhesins in SIV-infected rhesus macaques.
  • Production of transgenes in vivo leading to serum neutralizing activity against SIV.
  • Fusion of rhesus cluster of differentiation 4 (CD4) or single-chain antibody (4L6) with albumin to create fusion immunoadhesins.
  • Assessment of serum neutralizing titers against original and diverse SIV strains.
  • Evaluation of protection against high viral challenge doses and determination of in vivo longevity.

Main Results:

  • Antibody-based immunoadhesins achieved high neutralizing titers against the original SIV strain.
  • CD4-based immunoadhesins demonstrated broader neutralization across different SIV strains and potential protection against high viral doses.
  • Albumin-antibody fusion immunoadhesins provided strong, prolonged protection against SIV challenge.
  • Albumin-CD4 fusion immunoadhesins showed reduced specificity and overall effectiveness compared to antibody-based molecules.
  • Albumin-based immunoadhesins increased in vivo longevity but induced anti-immunoadhesin antibodies.

Conclusions:

  • Immunoadhesins delivered by rAAV vectors are a promising strategy for SIV neutralization.
  • Albumin fusion enhances the longevity of immunoadhesin-mediated protection but can introduce immunogenicity challenges.
  • CD4-based immunoadhesins offer a wider neutralization spectrum against SIV, suggesting potential for broader therapeutic application.