Adeno-associated virus (AAV) vectors have the potential to replace conventional anti-retroviral therapies, or even protect against an initial HIV-1 infection. The potential of AAV vectors arises from two properties: their exceptional safety profile, and their ability to sustain very high levels of transgene expression for years. A self-complementary AAV (scAAV) vector can sustain expression of 100-200 pg/ml of protein inhibitors for more than two years. In contrast, transgene expression from a conventional, single-stranded (ssAAV) vector is more than ten-fold lower. However, scAAV transgenes are necessarily half the size of ssAAV transgenes. This limit precludes expression of full-length antibodies, and instead requires use of non-native antibody-like molecules such as single-chain immunadhesins (scFv-Fc). Moreover, the size limitation of scAAV vectors prevents inclusion of other useful molecules, for example the joining (J) chains essential for IgA multimerization, and proteins and regulatory regions useful in various """"""""off-switch"""""""" strategies. It is therefore important to determine if ssAAV-expressed transgenes can suppress viral replication with efficiencies comparable to those achievable with scAAV vectors. This project will address this issue and then explore the contribution of the Fc regions of IgGI, lgG2, and IgA to suppresion of HIV-1 replication and transmission.
Aim 1 of this project seeks to enhance the transgene expression of ssAAV vectors expressing full-length antibodies, and determine if these improved vectors can suppress HIV-1 as effectively as scAAV-expressed transgenes.
Aim 2 asks whether antibody effector mechanisms other than neutralization contribute to suppression of HIV- 1 in vivo.
Aim 3 compares the usefulness of IgGI, lgG2 and IgA in limiting virus transmission. These studies will help determine which vectors, transgenes, and approaches can best suppress an ongoing HIV-1 infection, or prevent viral transmission.
Adeno-associated virus (AAV) vectors have the potential to replace conventional anti-retroviral therapies, or even protect against an initial HIV-1 infection. This project will evaluate several variations of AAV vectors and transgenes to determine which are best at controlling HIV-1 replication, and which are best at preventing HIV-1 transmission.
|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|
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