The 7 APOBEC3 genes (APOBEC3A, B, C, DE, F, G and H) in the human genome encode antiviral cytidine deaminases. The deaminases are specifically packaged into virions where they deaminate cytosine nucleotides in the minus-strand of the viral reverse transcripts. The Vif accessory protein counteracts APOBEC3F and G by binding and inducing their degradation. The project will investigate several features APOBEC3 biology.
Specific aim 1 will generate a panel of monoclonal antibodies against the family members and use these to characterize the tissue and cell-type expression of the individual family members. Each family member will be tested in stable cell lines to evaluate their antiviral activity against HIV-1 and SIV.
Specific aim 2 will investigate the transcriptional regulation of the APOBEC3 genes. Microarray expression profiling will be used to identify the transcription factors that regulate transcription of the APOBEC3 genes by finding expression differences between closely matched nonpermissive and permissive cells. Cellular genes will be identified that are co-regulated with APOBEC3G. Transcription factor binding sites in the APOBEC3G promoter will be identified to define how the gene is regulated and to provide insight into ways to influence promoter activity that would increase the intracellular levels of protective APOBEC3 proteins.
Specific aim 3 will investigate the mechanisms by which APOBEC3 proteins are packaged into virions will study the role of APOBEC3 in the mouse which has only a single APOBEC3 gene.
Specific aim 4 will use the mouse model to study the role of APOBEC3 in the immune response. The studies will make use of an APOBEC3 knock-out mouse to investigate the mechanism by which APOBEC3 suppresses retrovirus replication in vivo and whether the protein plays a role in the suppression of retrotransposons or a yet unidentified role in the immune system.
The APOBEC3 proteins are a family of 7 proteins that restrict the replication of viruses including HIV. The project will investigate the roles of the APOBEC3 family members to understand which ones are active against HIV-1 and how they interfere with the replication of the virus.
|Jáuregui, Paula; Landau, Nathaniel R (2018) DNA damage induces a SAMHD1-mediated block to the infection of macrophages by HIV-1. Sci Rep 8:4153|
|Vanwalscappel, Bénédicte; Tada, Takuya; Landau, Nathaniel R (2018) Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin. Virology 522:199-208|
|Bloch, Nicolin; Gläsker, Sabine; Sitaram, Poojitha et al. (2017) A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse. J Biol Chem 292:1068-1080|
|Norton, T D; Miller, E A; Bhardwaj, N et al. (2015) Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 22:227-36|
|Simon, Viviana; Bloch, Nicolin; Landau, Nathaniel R (2015) Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat Immunol 16:546-53|
|Jáuregui, Paula; Logue, Eric C; Schultz, Megan L et al. (2015) Degradation of SAMHD1 by Vpx Is Independent of Uncoating. J Virol 89:5701-13|
|Landau, Nathaniel R (2014) The innate immune response to HIV-1: to sense or not to sense. DNA Cell Biol 33:271-4|
|Minkah, Nana; Chavez, Kevin; Shah, Parth et al. (2014) Host restriction of murine gammaherpesvirus 68 replication by human APOBEC3 cytidine deaminases but not murine APOBEC3. Virology 454-455:215-26|
|Huber, Andrew D; Michailidis, Eleftherios; Schultz, Megan L et al. (2014) SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 58:4915-9|
|Bloch, Nicolin; O'Brien, Meagan; Norton, Thomas D et al. (2014) HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AIDS Res Hum Retroviruses 30:195-203|
Showing the most recent 10 out of 29 publications