Investigating the mechanism by which HIV mediates CD4 T-cell death, and the role of inflammation as a driver of HIV pathogenesis

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About Dr. Doitsh
Dr. Doitsh’s research focuses on the mechanisms by which HIV induces CD4 T-cell death, and the role of inflammation as a driver of HIV pathogenesis. Dr. Doitsh explores these questions using a unique, physiologically relevant experimental system formed of fresh human lymphoid cultures. In many regards, this system is one of the most powerful experimental approaches to modeling molecular and cellular events during HIV infection in human patients.
Prior to his current position at Gladstone, Dr. Doitsh received his postdoctoral training in the laboratory of Dr. Warner C. Greene, who directs virology and immunology research at Gladstone.

Dr. Doitsh earned a bachelor’s degree in biology at the Tel Aviv University in Israel. He then earned a master’s degree in molecular genetics, and a PhD in molecular genetics and virology at the Weizmann Institute of Science in Rehovot, Israel. Dr. Doitsh has authored many peer-reviewed publications in the fields of virology and viral-host cell interaction. He has received numerous awards and honors, including the The 2010 Gladstone Institute of Virology and Immunology Award for Scientific Excellence, The Robert John Sabo Trust Award for research into the causes and treatment of AIDS and Cancer, The NIH Exploratory/Developmental Research Grant Award (R21), and The Young Investigator Award from the 19th Conference on Retroviruses and Opportunistic Infections (CROI).

Areas of Investigation
Helper CD4 T cells are absolutely central players for the body’s immune response against foreign pathogens. As dramatically demonstrated in patients with acquired immunodeficiency syndrome (AIDS), a person lacking CD4 T cells cannot fend off many common microbes that are normally harmless. AIDS is caused by the human immunodeficiency virus (HIV), which promotes progressive depletion of CD4 T cells.

Despite vigorous research over the last 30 years, the precise mechanism underlying CD4 T-cell death in AIDS has remained poorly understood. The elucidation of this mechanism remains one of the top unsolved mysteries in HIV research. We explore the mechanisms by which HIV depletes CD4 T cells using a unique, physiological relevant experimental system formed with fresh human lymphoid cultures. In many regards, this system is one of the most powerful experimental ex vivo approaches for modeling the molecular and cellular events that occur during HIV infection in human patients. Extensive depletion of CD4 T cells occurs in these lymphoid cultures following infection with HIV. Surprisingly, we find that CD4 T cells are not dying because of a toxic action or products encoded by HIV. Rather, these cells are dying as a consequence of a powerful defensive response launched against the virus before it can make copies of itself. Our studies show that HIV enters the target CD4 T cells and begins reverse transcription. However, during this process, incomplete viral DNA intermediates that accumulate in the cytoplasm are sensed and trigger innate antiviral suicidal response in attempt to eliminate the viral spread.

A second surprise was our discovery that the mechanism of CD4 T-cell death was not “silent”. Instead, these infected cells die a fiery death known as pyroptosis, causing significant inflammation as they erupt their cellular contents and release chemical signals, which recruit healthy CD4 T cells to the site of infection. These events may establish a vicious cycle in HIV patients, where dying CD4 T cells release inflammatory signals that attract more cells to die.

Current Lab Focus

  1. Exploring the role of pyroptosis and inflammation in HIV pathogenesis, and indentifying the inflammasome that activates caspase-1-mediated responses in HIV-infected CD4 T cells.
  2. Identifying the cytoplasmic sensor(s) that detect HIV DNA reverse transcripts in lymphoid CD4 T cells and elicit innate immune and inflammatory suicide responses.
  3. Investigating the cytopathic effects of HIV in CD4 T cells from peripheral blood and gut-associated lymphoid tissues.
  4. Exploring the strategies that HIV employs to evade detection by innate immunity.

 
Joined Gladstone in 2004

Why Gladstone?
While the Gladstone is compact in size, it is comprised of heterogeneous research units and state of the art Core labs. Most importantly, Gladstone is home to a community of excellent scientists from all over the world, which creates an inspiring, stimulating, and creative work environment. Together, these aspects promote a deeper and more insightful understanding into the biology of human disease.