The broad purpose of this program-project is to show that advances AAV-based gene therapy enable stable, long-term suppression of HIV-1 replication. Our immediate goal is to stably suppress an ongoing SHIV-infection in rhesus macaques, using specific combinations of antiviral proteins delivered by self-complementary AAV vectors. Any effective therapy for HIV-1 infection has to solve the problem of viral escape. This project addresses the problem of viral escape from a cocktail of antibodies iteratively, by rapidly identifying viral escape pathways and adjusting these cocktails so that these pathways are blocked. We are aided in this effort by a variant of CD4-Ig, fused to a 14-amino-acid peptide that closely mimics a high-affinity binding region of CCR5. This enhanced CD4-Ig (

Public Health Relevance

Adeno-associated virus (AAV) vectors expressing HIV-1 neutralizing antibodies have the potential to replace current anti-retroviral combination therapies. However, the problem of viral escape from these protein inhibitors must be solved before AAV expressed transgenes can be useful therapeutically. In this project we address this critical problem of viral escape, and improve several HIV-1 neutralizing antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI100263-01
Application #
8311213
Study Section
Special Emphasis Panel (ZAI1-RB-A (J1))
Project Start
2012-04-01
Project End
2012-11-30
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$441,853
Indirect Cost
$111,853
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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Wang, Dan; Gao, Guangping (2014) State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications. Discov Med 18:151-61
Gao, Kai; Li, Mengxin; Zhong, Li et al. (2014) Empty Virions In AAV8 Vector Preparations Reduce Transduction Efficiency And May Cause Total Viral Particle Dose-Limiting Side-Effects. Mol Ther Methods Clin Dev 1:20139
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Venkatesh, Aditya; Ma, Shan; Langellotto, Fernanda et al. (2013) Retinal gene delivery by rAAV and DNA electroporation. Curr Protoc Microbiol Chapter 14:Unit 14D.4
Ahmed, Seemin Seher; Li, Jia; Godwin, Jonathan et al. (2013) Gene transfer in the liver using recombinant adeno-associated virus. Curr Protoc Microbiol Chapter 14:Unit14D.6