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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-RB-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Florida
United States
Zip Code
Martinez-Navio, José M; Fuchs, Sebastian P; Pedreño-López, Sònia et al. (2016) Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. Mol Ther 24:76-86
Gardner, Matthew R; Fellinger, Christoph H; Prasad, Neha R et al. (2016) CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies. J Virol 90:7822-32
Rashnonejad, Afrooz; Chermahini, Gholamhossein Amini; Li, Shaoyong et al. (2016) Large-Scale Production of Adeno-Associated Viral Vector Serotype-9 Carrying the Human Survival Motor Neuron Gene. Mol Biotechnol 58:30-6
Xie, Jun; Burt, Daniel Robert; Gao, Guangping (2015) Adeno-associated virus-mediated microRNA delivery and therapeutics. Semin Liver Dis 35:81-8
Wang, Dan; Mou, Haiwei; Li, Shaoyong et al. (2015) Adenovirus-Mediated Somatic Genome Editing of Pten by CRISPR/Cas9 in Mouse Liver in Spite of Cas9-Specific Immune Responses. Hum Gene Ther 26:432-42
Fuchs, Sebastian P; Martinez-Navio, José M; Piatak Jr, Michael et al. (2015) AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity. PLoS Pathog 11:e1005090
Gardner, Matthew R; Kattenhorn, Lisa M; Kondur, Hema R et al. (2015) AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519:87-91
Ahmed, Seemin S; Gao, Guangping (2015) Making the White Matter Matters: Progress in Understanding Canavan's Disease and Therapeutic Interventions Through Eight Decades. JIMD Rep 19:11-22
Wang, Dan; Gao, Guangping (2014) State-of-the-art human gene therapy: part I. Gene delivery technologies. Discov Med 18:67-77
Quinlan, Brian D; Joshi, Vinita R; Gardner, Matthew R et al. (2014) A double-mimetic peptide efficiently neutralizes HIV-1 by bridging the CD4- and coreceptor-binding sites of gp120. J Virol 88:3353-8

Showing the most recent 10 out of 22 publications