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

Areas of Investigation
We focus on virus-host cell interactions of two pathogens, the human immunodeficiency virus (HIV-1) and the hepatitis C virus (HCV). We focus specifically on molecular mechanisms of HIV transcription and latency, the central role of the HIV transactivator Tat and its control of HIV transcription elongation and T cell activation. In HCV research, we study lipid droplets as an emerging assembly platform for HCV virions and the interactions of viral proteins with fat metabolism and mitochondria in infected liver cells.

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 23ñ75% 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

• The HCV core protein interacts with the triglyceride-synthesizing enzyme DGAT1 in HCV-infected liver cells, and this interaction recruits core from the endoplasmic reticulum to the surface of lipid droplets (Herker et al, Nat Med, 2010).
• We identified a new posttranslational modification in Tat, monomethylation at K51 that enhances interactions of Tat with TAR RNA and the transcription elongation factor P-TEFb. (Pagans et al, Cell Host Microbe, 2010)
• The transcriptional activity of P-TEFb is regulated by acetylation of four lysine residues in the coiled-coil region of the cyclin T1 subunit (Cho et al, EMBO J, 2009)
• Tat inhibits the NAD+ deacetylase SIRT1 and enhances T cell activation via hyperacetylation of K310 in the p65 subunit of the NF-κB transcription factor (Kwon et al, Cell Host Microbe, 2008).

Some questions addressed in ongoing studies

• Why is DGAT1 and not its sister enzyme DGAT2 a target of HCV infection?
• What is the comprehensive proteome of Tat modifications in infected cells?
• What is the immune-regulatory function of SIRT1 in T cells?
• Can enzymes modifying Tat be targeted therapeutically to treat HIV infection/latency?