Melanie Ott, M.D., Ph.D
Associate Investigator
Gladstone Institute of Virology and Immunology
Assistant Professor of Medicine
University of California, San Francisco
Email: mott@gladstone.ucsf.edu
Telephone: 415-734-4807
Fax: 415-355-0855

Areas of Investigation
We focus primarily on the molecular mechanisms of HIV-1 Tat transactivation. Our specific interests are the role of reversible Tat acetylation in HIV transcription and Tat’s recruitment of histone-modifying enzymes. We recently expanded our efforts to include the pathogenesis of hepatitis C virus (HCV) infection, particularly the influence of the HCV core protein on host cell functions during HCV infection.

Significance
Complications from HCV infection are becoming one of the most important medical issues facing HIV-infected individuals. Worldwide, it is estimated that 170 million people are infected with HCV; 36.1 million of those are living with HIV/AIDS, and 23–75% of HIV-infected individuals may be coinfected with HIV/HCV. The HIV transactivator Tat and the HCV capsid protein core play central roles in the pathogenesis of HIV and HCV infections. Understanding the biology of these proteins will promote the development of novel therapeutic strategies against progressive HIV/HCV disease.

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Approaches
We use a variety of molecular biology techniques in several tumor and primary cell cultures, including retroviral and lentiviral vector systems, nuclear and cytoplasmic microinjections, HIV infection of T cells and T-cell lines and studies of Huh-7 hepatoma cells infected with an infectious clone of HCV. We study transgenic mice conditionally expressing HCV core in the liver and SIRT1 knock-out mice. We have access to clinical samples through colleagues at Gladstone and the UCSF Liver Center.

Contributions

• Tat is acetylated by the acetyltransferase activity of p300 and deacetylated by the NAD+-dependent deacetylase SIRT1.
• Tat acetylation generates a novel protein:protein interface with bromodomain-containing proteins including PCAF.
• Tat inhibits the SIRT1 deacetylase and induces T-cell hyperactivation in HIV-infected T cells.
• A fraction of HCV core is targeted to the outer mitochondrial membrane via a C-terminal localization motif.

Some questions addressed in ongoing studies

• What is the function of bromodomain-containing proteins recruited by acetylated Tat?
• What is the role of SIRT1 in HIV-infected T cells?
• What is the contribution of mitochondrial core to HCV pathogenesis?