AIDS Caused by Cellular Functions, Not HIV

Cell-to-cell transmission of HIV causes greater CD4 T cell death.

Cell-to-cell transmission of HIV causes greater CD4 T cell death.

HIV does not cause AIDS by its own fault; rather, it is our own cellular functions that transform HIV into AIDS, according to a new study from the Gladstone Institutes.

HIV can be spread in one of two ways: virally or through cell-to-cell transmission. When HIV is spread through cell-to-cell transmission, it is 100 to 1000 times more effective in spreading the disease, setting off a cellular chain reaction that ends in the newly infected cells self-destructing.

“The fundamental ‘killing units’ of CD4 T cells in lymphoid tissues are other infected cells, not the free virus,” said co-first author Gilad Doitsh, PhD, a staff research investigator at the Gladstone Institute of Virology and Immunology. “And cell-to-cell transmission of HIV is required for activation of the main HIV death pathway.”

Studies in the past have shown that 95% of cell death from HIV is caused by immune cells committing suicide in order to save themselves from infection. When the virus tries to invade a cell that is “at rest,” the infection is aborted.

However, viral DNA fragments remain and are detected by the resting host cell. This triggers a chain reaction in the cell’s defense system, activating the enzyme caspase-1, which ultimately causes the induction of self-destruction.

The new study reports that this death pathway is only activated through cell-to-cell transmission of HIV. It does not occur from viral infection.

The scientists compared cell death rates in cell-to-cell transmission and free virus transfer using lymphoid tissue infected with HIV. The results revealed that while overall rates of infection remained the same, there was more CD4 T cell death if HIV was spread via cell-to-cell transmission, rather than free-floating viral infection.

“Although free-floating viruses establish the initial infection, it is the subsequent cell-to-cell spread of HIV that causes massive CD4 T cell death,” said co-first author Nicole Galloway, PhD, a post-doctoral fellow at the Gladstone Institute of Virology and Immunology. “Cell-to-cell transmission of HIV is absolutely required for activation of the pathogenic HIV cell-death pathway.”

The researchers tested their findings by disturbing a viral transfer through a number of means, including genetically modifying the virus; applying chemical HIV inhibitors; blocking inter-cellular synapses; and increasing the physical distance between the cells so they could not come into contact with one another.

Interference with cell-to-cell contact effectively stopped the death of CD4 T cells. Additionally, scientists found that caspase-1 was only activated during cell-to-cell transmission, thereby initiating self-destructive behaviors in the cells.

Scientists point to the efficiency of cell-to-cell transmission to explain the difference in cell death rates between the two methods of infection. Aborted viral DNA fragments are quickly removed during infection by cell-free HIV particles, so they are not detected by the cell’s defensive system.

In cell-to-cell transmission, viral DNA fragments negatively affect cell maintenance, building up until they pass a certain point and are detected, activating caspase-1 and triggering cell suicide.

“This study fundamentally changes our mindset about how HIV causes massive cell death, and puts the spotlight squarely on the infected cells in lymphoid tissues rather than the free virus,” said senior author Warner C. Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology. “By preventing cell-to-cell transmission, we may be able to block the death pathway and stop the progression from HIV infection to AIDS.”