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AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.

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Adeno-associated virus (AAV) vectors delivering eCD4-Ig, a potent HIV-1 entry inhibitor, offer a potential vaccine alternative. This approach demonstrated protection in macaques against simian-human immunodeficiency virus challenges.

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Area of Science:

  • Virology
  • Immunology
  • Gene Therapy

Background:

  • Conventional vaccines for Human Immunodeficiency Virus type 1 (HIV-1) are challenging to develop.
  • Adeno-associated virus (AAV) vectors can achieve long-term expression of broadly neutralizing antibodies (bNAbs) for HIV-1.
  • Existing bNAbs show limited efficacy against a significant fraction of HIV-1 isolates.

Purpose of the Study:

  • To evaluate the potential of eCD4-Ig, a novel entry inhibitor, as an alternative to conventional HIV-1 vaccines.
  • To assess the in vivo efficacy and immunogenicity of AAV-delivered eCD4-Ig in a non-human primate model.

Main Methods:

  • Development of eCD4-Ig, a fusion protein combining CD4-Ig and a CCR5-mimetic sulfopeptide.
  • In vitro neutralization assays against diverse HIV-1, HIV-2, and simian immunodeficiency virus isolates.
  • In vivo studies in rhesus macaques using AAV vectors to deliver eCD4-Ig, followed by simian-human immunodeficiency virus (SHIV) challenge.

Main Results:

  • eCD4-Ig demonstrated potent and broad neutralization activity against a wide range of HIV isolates, surpassing existing bNAbs.
  • AAV-mediated expression of eCD4-Ig in rhesus macaques was sustained for over 40 weeks.
  • Macaques expressing eCD4-Ig were protected from SHIV-AD8 challenge and showed reduced immunogenicity compared to bNAbs.

Conclusions:

  • AAV-delivered eCD4-Ig represents a promising strategy for long-term protection against HIV-1 infection.
  • This gene therapy approach could serve as a functional vaccine, circumventing the need for traditional vaccination methods.