The human APOBECSG and APOBECSF (ASG/F) proteins restrict the ability of retroviruses, including HIV-1, to successfully infect cells. This defense is caused by deamination of nascent dC residues, converting them to dU in the cDNA strand of the replicating HlV-1. The resulting mutated viral DNA leads to functional inactivation of the invading virus. As a counter-defense, HIV-1 and other lentiviruses express Vif which mediates the degradation of ASs by the cellular proteasome machinery. HlV-1 replication is completely blocked when the interaction between ASG/Vif is prevented, pointing at the potentiality of ASG as an antiviral agent. We therefore speculate that preventing ASG/F/Vif interaction or enhancing A3G/F activity in the cells may prevail over Vif activity, enabling the host cell defense machinery to halt the production of infectious virus. The overall goal of this study is to define small molecules, which will allow ASG/F to neutralize HlV-1 in its natural target cells. A better understanding of the mechanism by which A3G/F hypermutates the viral DNA and the way(s) Vif counteracts this activity is essential for designing these compounds.
Our specific aims are to (i) determine the impact of ASG/F oligomerization on deaminase activity and other biochemical properties, (ii) determine the biochemical properties of ASG/F interaction with single-stranded DNA, and (iii) evaluate compounds that modulate ASG/F/Vif interactions.
These aims will be achieved by applying biochemical and biophysical approaches;and particulariy a novel quantitative DNA deaminase assay, to understand the DNA deaminase activity of ASG/F and ASG/F variants, and by analyzing the activity of A3G/F in the presence/absence of Vif and/or Vif fragments/peptides.
Our results will assist in designing small compounds which prevent ASG/F/Vif interaction(s), allowing ASG/F to act as a natural and efficient antiviral agent. These new molecules will be used as lead compounds for designing anti-HIV-1 drugs. Such drugs may be very effective, because they target genetically stable cellular protein(s) and because neutralizing Vif/A3G/F interaction should not be detrimental to ceils.
| Silvas, Tania V; Hou, Shurong; Myint, Wazo et al. (2018) Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions. Sci Rep 8:7511 |
| Pan, Yangang; Sun, Zhiqiang; Maiti, Atanu et al. (2017) Nanoscale Characterization of Interaction of APOBEC3G with RNA. Biochemistry 56:1473-1481 |
| Richards, Christopher M; Li, Ming; Perkins, Angela L et al. (2017) Reassessing APOBEC3G Inhibition by HIV-1 Vif-Derived Peptides. J Mol Biol 429:88-96 |
| Kouno, Takahide; Silvas, Tania V; Hilbert, Brendan J et al. (2017) Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity. Nat Commun 8:15024 |
| Khisamutdinov, Emil F; Jasinski, Daniel L; Li, Hui et al. (2016) Fabrication of RNA 3D Nanoprisms for Loading and Protection of Small RNAs and Model Drugs. Adv Mater 28:10079-10087 |
| Li, Jinhui; Barylko, Barbara; Eichorst, John P et al. (2016) Association of Endophilin B1 with Cytoplasmic Vesicles. Biophys J 111:565-576 |
| Shlyakhtenko, Luda S; Dutta, Samrat; Li, Ming et al. (2016) Single-Molecule Force Spectroscopy Studies of APOBEC3A-Single-Stranded DNA Complexes. Biochemistry 55:3102-6 |
| Yoshikawa, Rokusuke; Izumi, Taisuke; Yamada, Eri et al. (2016) A Naturally Occurring Domestic Cat APOBEC3 Variant Confers Resistance to Feline Immunodeficiency Virus Infection. J Virol 90:474-85 |
| Sharma, Ashwani; Haque, Farzin; Pi, Fengmei et al. (2016) Controllable self-assembly of RNA dendrimers. Nanomedicine 12:835-844 |
| Lyubchenko, Yuri L; Shlyakhtenko, Luda S (2016) Imaging of DNA and Protein-DNA Complexes with Atomic Force Microscopy. Crit Rev Eukaryot Gene Expr 26:63-96 |
Showing the most recent 10 out of 83 publications
