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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058864-09
Application #
8287114
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Miller, Roger H
Project Start
2004-01-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$418,275
Indirect Cost
$170,775
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Logue, Eric C; Bloch, Nicolin; Dhuey, Erica et al. (2014) A DNA sequence recognition loop on APOBEC3A controls substrate specificity. PLoS One 9:e97062
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
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Schrofelbauer, Barbel; Hakata, Yoshiyuki; Landau, Nathaniel R (2007) HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc Natl Acad Sci U S A 104:4130-5

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