Scientists at Gladstone Institute of Virology and Immunology have determined how HIV promotes the death of CD4 T cells. Their study also revealed a new mechanism linking the virus to inflammation. The findings appear in the November 24 issue of Cell.
Most immune cells that die during HIV infection are seemingly not infected, a phenomenon called bystander cell killing. The Gladstone team says that these bystander cells are actually the victims of a failed or abortive form of viral infection.
“Our study reveals that the virus actually enters the CD4 T cells that are destined to die and that the virus starts to make a DNA copy of its RNA, a process called reverse transcription,” explains Gilad Doitsh, Ph.D., lead author of the paper. “However, this process does not work well in the majority of these cells, and the incomplete DNA intermediates that accumulate in the cytoplasm are sensed and trigger the cells to commit suicide in an attempt to protect the body.”
The researchers identified the precise step in which the CD4 T cells die by using different anti-HIV drugs to arrest the virus at different points in its life cycle. Drugs that blocked viral entry or that blocked the start of reverse transcription stopped the killing. Conversely, drugs that acted later in the life cycle did not.
The investigators used primary human lymphoid tissues, such as tonsil and spleen to uncover this death pathway. These and other lymphoid tissues contain over 98% of the body's CD4 T cells and represent the major site where the virus reproduces itself.
The team also found that as the CD4 T cells die, they release cytokines that cause inflammation and that attract healthy cellular targets, promoting repeated rounds of infection and cell death.
“These results highlight how a natural cellular defense normally used by the host to repel foreign invaders goes awry in HIV infection, resulting in a profound depletion of CD4 T cells,” says Warner C. Greene, M.D., Ph.D., institute director and senior author of the paper. “If untreated, this process ultimately causes AIDS.”