APOBEC3G/CEM15 Inhibition of Lentivirus Replication

Summary

Principal Investigator: Nathaniel R Landau
Abstract: 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.
Funding Period: 2013-08-16 - 2015-08-15
more information: NIH RePORT

Top Publications

  1. ncbi APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons
    Hui Chen
    Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Curr Biol 16:480-5. 2006
  2. pmc Host restriction of murine gammaherpesvirus 68 replication by human APOBEC3 cytidine deaminases but not murine APOBEC3
    Nana Minkah
    Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA
    Virology 454:215-26. 2014
  3. pmc The innate immune response to HIV-1: to sense or not to sense
    Nathaniel R Landau
    Department of Microbiology, NYU School of Medicine, New York, New York
    DNA Cell Biol 33:271-4. 2014
  4. pmc SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells
    Ruonan Zhang
    Department of Microbiology, NYU School of Medicine, New York, New York, United States of America
    PLoS ONE 9:e89558. 2014
  5. pmc Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated restriction of HIV-1
    Henning Hofmann
    Microbiology Department, New York University School of Medicine, New York, New York, USA
    J Virol 87:11741-50. 2013
  6. pmc Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx
    Thomas Gramberg
    New York University School of Medicine, Microbiology Department, 522 First Ave, New York, NY 10016, USA
    J Virol 84:1387-96. 2010
  7. pmc Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase
    Iñigo Narvaiza
    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA
    PLoS Pathog 5:e1000439. 2009
  8. pmc Restriction of HIV-1 by APOBEC3G is cytidine deaminase-dependent
    Edward P Browne
    Department of Microbiology, New York University School of Medicine, New York, 10016, USA
    Virology 387:313-21. 2009
  9. pmc HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1
    Bärbel Schröfelbauer
    Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037 1099, USA
    Proc Natl Acad Sci U S A 104:4130-5. 2007
  10. pmc Analysis of Vif-induced APOBEC3G degradation using an alpha-complementation assay
    Lei Fang
    Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037 1099, USA
    Virology 359:162-9. 2007

Detail Information

Publications12

  1. ncbi APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons
    Hui Chen
    Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Curr Biol 16:480-5. 2006
    ..They also highlight the functional differences between APOBEC3 proteins. The APOBEC3 family members have distinct functions and may have evolved to resist various classes of genetic elements...
  2. pmc Host restriction of murine gammaherpesvirus 68 replication by human APOBEC3 cytidine deaminases but not murine APOBEC3
    Nana Minkah
    Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA
    Virology 454:215-26. 2014
    ..We infer that mA3 does not restrict wild type MHV68 and restriction by human A3s may be limited in the herpesvirus replication process...
  3. pmc The innate immune response to HIV-1: to sense or not to sense
    Nathaniel R Landau
    Department of Microbiology, NYU School of Medicine, New York, New York
    DNA Cell Biol 33:271-4. 2014
    ..This article reviews the recent findings and discusses the similarities and differences. ..
  4. pmc SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells
    Ruonan Zhang
    Department of Microbiology, NYU School of Medicine, New York, New York, United States of America
    PLoS ONE 9:e89558. 2014
    ..Our findings suggest that the role of SAMHD1 in restricting viruses is conserved in the mouse. The RAW264.7 cell-line serves as a useful tool to study the antiviral and innate immune response functions of SAMHD1. ..
  5. pmc Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated restriction of HIV-1
    Henning Hofmann
    Microbiology Department, New York University School of Medicine, New York, New York, USA
    J Virol 87:11741-50. 2013
    ..Taken together, these findings support deoxynucleoside triphosphate pool depletion as the primary mechanism of SAMHD1 restriction and argue against a nucleolytic mechanism, which would not be reversible. ..
  6. pmc Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx
    Thomas Gramberg
    New York University School of Medicine, Microbiology Department, 522 First Ave, New York, NY 10016, USA
    J Virol 84:1387-96. 2010
    ..These findings suggest that the Vpx amino terminus contains an activation domain that serves as the binding site for a cellular restriction factor...
  7. pmc Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase
    Iñigo Narvaiza
    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA
    PLoS Pathog 5:e1000439. 2009
    ..In summary, our results demonstrate that deaminase activity is not necessary for the antiviral activity of A3A against parvoviruses...
  8. pmc Restriction of HIV-1 by APOBEC3G is cytidine deaminase-dependent
    Edward P Browne
    Department of Microbiology, New York University School of Medicine, New York, 10016, USA
    Virology 387:313-21. 2009
    ..We conclude that cytidine deamination is the mechanism by which APOBEC3G restricts HIV-1...
  9. pmc HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1
    Bärbel Schröfelbauer
    Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037 1099, USA
    Proc Natl Acad Sci U S A 104:4130-5. 2007
    ..The interaction with DDB1 may explain several of the diverse biological functions of Vpr and suggests potential roles for Vpr in HIV-1 replication...
  10. pmc Analysis of Vif-induced APOBEC3G degradation using an alpha-complementation assay
    Lei Fang
    Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037 1099, USA
    Virology 359:162-9. 2007
    ..These findings support hA3G degradation as a requirement for Vif function. The Vif alpha-complementation assay may be a useful tool for the identification of Vif inhibitors...
  11. ncbi Reversed functional organization of mouse and human APOBEC3 cytidine deaminase domains
    Yoshiyuki Hakata
    Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    J Biol Chem 281:36624-31. 2006
    ..Deaminase-independent antiviral activity of the active site mutants was minor. These findings suggest that the two active sites have different functions but that these functions can be interchanged in different APOBEC3 family members...
  12. pmc A DNA sequence recognition loop on APOBEC3A controls substrate specificity
    Eric C Logue
    Department of Microbiology, NYU School of Medicine, New York, New York, United States of America
    PLoS ONE 9:e97062. 2014
    ..These findings shed light on how APOBEC3 proteins bind their substrate and determine which sites to deaminate. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Mechanisms of APOBEC3A Inhibition
    Matthew D Weitzman; Fiscal Year: 2013
    ..This combination provides a unique niche in which to examine APOBEC functions and unravel mechanisms responsible for a range of antiviral activities. ..
  3. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  4. Genomic Determinants of Intrinsic Antiviral Host Defenses
    VIVIANA A SIMON; Fiscal Year: 2013
    ..In addition, understanding the functional diversity of intrinsic defense factors has the potential to create novel treatment strategies aimed at a long- lasting suppression of HIV/AIDS disease. ..
  5. Innate Restriction Factor Modulation of Retrovirus-specific Humoral Immunity
    MARIO LUIS SANTIAGO; Fiscal Year: 2013
    ..Detailed insights on the interplay between Apobec3-mediated innate immunity and retrovirus-specific neutralizing antibody development may critically guide the construction and evaluation of HIV vaccines. ..
  6. Protein homeostasis mechanisms underlying enterovirus replication and evolution
    Raul Andino; Fiscal Year: 2013
    ..Core A: Administrative Core;and Core B: "High-throughput functional genomics and proteomics core. ..
  7. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
    Dennis R Burton; Fiscal Year: 2013
    ..The team will be sustained by five Scientific Research Support Components (SRSCs), including strong Operations and Management, that have been assembled to maximally accelerate progress toward the designated goals. ..
  8. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  9. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  10. The Center for HIV RNA Studies (CRNA)
    Alice Telesnitsky; Fiscal Year: 2013
    ..These studies will also result in the development of novel techniques that can be applied to all areas of RNA biology. ..
  11. HTLV-1 antagonists of HIV restriction factors
    VIVIANA A SIMON; Fiscal Year: 2013
    ....
  12. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  13. Role of APOBEC3 in in vivo Restriction of Retrovirus Infection
    Susan R Ross; Fiscal Year: 2013
    ..These studies will provide insight into how APOBEC3 proteins inhibit infection by human retroviruses such as HIV-1 in an experimentally tractable mouse model. ..
  14. HIV-1: microRNA interactions
    Bryan R Cullen; Fiscal Year: 2013
    ..This research has the potential to not only shed new light on HIV-1 pathogenesis but also suggest new approaches to inhibit virus replication. ..
  15. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  16. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  17. The in vivo function of A3A and A3G during retrovirus infection
    Spyridon Stavrou; Fiscal Year: 2013
    ..This study will provide insight into the function of the A3 proteins in vivo, and also has the potential to create new models for testing therapeutic strategies for treating retroviral infections in humans. ..
  18. Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology
    CHARLES NICHOLAS SERHAN; Fiscal Year: 2013
    ..Selected synthetic SPM will be scaled-up for demonstration of their unique mode of action in vivo in a resolution pharmacology core using experimental disease models. Our broad goal is to bring forth new treatments in resolution. ..
  19. Mechanisms of innate immunity against HIV
    Tariq M Rana; Fiscal Year: 2013
    ..In addition, cellular genes that are modulated by RNAI machinery during HIV infection would identify new candidates for drug development. ..
  20. Determining the role of human endogenous retroviruses (HERV) in HIV-1 infection
    Devi SenGupta; Fiscal Year: 2013
    ....
  21. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  22. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  23. Novel Ad/MVA and Ad/Protein HIV-1 Vaccines
    Dan H Barouch; Fiscal Year: 2013
    ..To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys. ..