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.
|Gessler, Dominic J; Li, Danning; Xu, Hongxia et al. (2017) Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease. JCI Insight 2:e90807|
|Ai, Jianzhong; Tai, Phillip W L; Lu, Yi et al. (2017) Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue. Prostate 77:1265-1270|
|Li, Dongxiao; Liu, Chong; Yang, Chunxing et al. (2017) Slow Intrathecal Injection of rAAVrh10 Enhances its Transduction of Spinal Cord and Therapeutic Efficacy in a Mutant SOD1 Model of ALS. Neuroscience 365:192-205|
|Ai, Jianzhong; Li, Jia; Gessler, Dominic J et al. (2017) Adeno-associated virus serotype rh.10 displays strong muscle tropism following intraperitoneal delivery. Sci Rep 7:40336|
|Fellinger, Christoph H; Gardner, Matthew R; Bailey, Charles C et al. (2017) Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4. J Virol 91:|
|Gardner, Matthew R; Farzan, Michael (2017) Engineering antibody-like inhibitors to prevent and treat HIV-1 infection. Curr Opin HIV AIDS :|
|Xie, Jun; Mao, Qin; Tai, Phillip W L et al. (2017) Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity. Mol Ther 25:1363-1374|
|Davis-Gardner, Meredith E; Gardner, Matthew R; Alfant, Barnett et al. (2017) eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. PLoS Pathog 13:e1006786|
|Tang, Maoxue; Gao, Guangping; Rueda, Carlos B et al. (2017) Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein. Nat Commun 8:14152|
|Zhong, Guocai; Wang, Haimin; Li, Yujun et al. (2017) Cpf1 proteins excise CRISPR RNAs from mRNA transcripts in mammalian cells. Nat Chem Biol 13:839-841|
Showing the most recent 10 out of 34 publications