Recombinant adeno-associated virus (AAV) vectors can safely deliver long-term (>2 years), high-titers (>200 ?g/ml) of antibody-like inhibitors to rhesus macaques. These titers are well above the IC90s of several broadly neutralizing HIV-1 antibodies. AAV vectors have an established safety record in humans, and risks associated with their use are modest, arguably lower than those associated with current antiviral regimens. If key hurdles can be surmounted, AAV-expressed transgenes could replace less-tolerated components of current combination therapies, or supplant these therapies entirely. An AAV-based approach would avoid toxicities, costs, and compliance concerns associated with current therapies. However some challenges remain. First, more experience with these vectors will be necessary to further increase confidence in their safety. Second, the relative in vivo efficacy of well-known HIV-1 neutralizing antibodies remains poorly described, especially in combination. Third, HIV-1 can escape antibodies passively administered to infected humans, although limitations of antibodies tested may have accelerated this escape. Finally, a minority of AAV-inoculated immune-sufficient macaques raise antibodies to and thereby clear expressed transgenes. The core purpose of these projects is to show that advances in AAV-based gene therapy now make possible 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 AAV vectors. To do so, we will address directly the key challenges of safety, efficacy, viral escape, and immune clearance of expressed transgenes. We have assembled a team with outstanding, complementary experience in macaque models of infection (Ronald Desrosiers, Harvard Medical School), therapeutic use of AAV transgenes (Guangping Gao, U Mass Medical School), HIV-1 entry and its inhibition with neutralizing antibodies (Michael Farzan, Harvard Medical School), and phage-based development and improvement of human antibodies (MSM Protein Technologies, led by Tajib Mirzabekov). We first focus on the common goal of establishing of a system in which viral loads in SHIV-infected animals can be reproducibly suppressed. Aspects of this baseline system will then be optimized to increase transgene efficacy (Projects 1 and 3), prevent immune clearance (Projects 1 and 2), and limit viral escape (Projects 3 and 4). These studies will establish principles and protocols directly applicable to subsequent human clinical trials.

Public Health Relevance

Recombinant AAV-delivered transgenes have the potential to supplement or even replace conventional combination antiviral therapies, and have considerable advantages over these therapies. This program project will optimize the efficacy of AAV-delivered HIV-1 neutralizing antibodies and address the key hurdles of immune elimination of expressed transgenes and viral escape. In doing so, they will inform and motivate similar efforts in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI100263-01
Application #
8305258
Study Section
Special Emphasis Panel (ZAI1-RB-A (J1))
Program Officer
Conley, Tony J
Project Start
2012-04-01
Project End
2012-11-30
Budget Start
2012-04-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$2,225,513
Indirect Cost
$563,377
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Dan; Li, Jia; Song, Chun-Qing et al. (2018) Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat Biotechnol 36:839-842
Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E et al. (2018) eCD4-Ig Variants That More Potently Neutralize HIV-1. J Virol 92:
Yoon, Yeonsoo; Wang, Dan; Tai, Phillip W L et al. (2018) Streamlined ex vivo and in vivo genome editing in mouse embryos using recombinant adeno-associated viruses. Nat Commun 9:412
Zhang, Wei; Li, Linjing; Su, Qin et al. (2018) Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis. Hum Gene Ther 29:42-50
Tai, Phillip W L; Xie, Jun; Fong, Kaiyuen et al. (2018) Adeno-associated Virus Genome Population Sequencing Achieves Full Vector Genome Resolution and Reveals Human-Vector Chimeras. Mol Ther Methods Clin Dev 9:130-141
Mou, Huihui; Zhong, Guocai; Gardner, Matthew R et al. (2018) Conditional Regulation of Gene Expression by Ligand-Induced Occlusion of a MicroRNA Target Sequence. Mol Ther 26:1277-1286
Wang, Dan; Gao, Guangping (2018) Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB. Mol Ther 26:336-338
Wang, Dan; Li, Jia; Tran, Karen et al. (2018) Slow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space. Hum Gene Ther Methods 29:75-85
Wang, Dan; Li, Shaoyong; Gessler, Dominic J et al. (2018) A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates. Mol Ther Methods Clin Dev 9:234-246
Lu, Yi; Tai, Phillip W L; Ai, Jianzhong et al. (2018) Transcriptome Profiling of Neovascularized Corneas Reveals miR-204 as a Multi-target Biotherapy Deliverable by rAAVs. Mol Ther Nucleic Acids 10:349-360

Showing the most recent 10 out of 46 publications