HIV Particles Do Not Cause AIDS, Our Own Immune Cells Do
The virus turns host immune cells into suicide machines, using them to spread the virus and cause the progression from HIV to AIDS
August 27, 2015 - SAN FRANCISCO, CA - Researchers from the Gladstone Institutes have
revealed that HIV does not cause AIDS by the virus’s direct effect on the host’s immune cells, but
rather through the cells’ lethal influence on one another.
HIV can either be spread through free-floating virus that directly infect the host immune cells or an
infected cell can pass the virus to an uninfected cell. The second method, cell to cell transmission,
is 100 to 1000 times more efficient, and the new study shows that it is only this method that sets
off a cellular chain reaction that ends in the newly infected cells committing suicide.
“The fundamental ‘killing units' of CD4 T cells in lymphoid tissues are other infected cells, not
the free virus,” says 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.”
In a previous investigation, the scientists
discovered that 95% of cell death from HIV is caused by immune cells committing suicide in self-defense
after an unsuccessful infection. When the virus tries to invade a cell that is “at rest,” the
infection is aborted. However, fragments of viral DNA remain and are detected by the resting
host cell. This triggers a domino effect in the cell's defense system, resulting in the
activation of the enzyme caspase-1, which ultimately causes the induction of
pyroptosis, a fiery form of cell suicide.
In the new study, published in Cell Reports , it was revealed that this death pathway is only activated
through cell-to-cell transmission of HIV, not from infection by free-floating viral particles. Using
lymphoid tissue infected with HIV, the scientists compared cell death rates between cell-to-cell
and cell-free virus transfer. They discovered that while overall rates of infection remained
the same, there was significantly more CD4 T cell death if HIV was spread by infection from
other cells than by free-floating virus.
“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,” says 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.”
To confirm this finding, the researchers perturbed viral transfer through a number of
means: 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. Notably, disruption of
cell-to-cell contact effectively stopped the death of CD4 T cells. What's
more, only during cell-to-cell transmission was caspase-1 activated
within the target cells, thereby initiating pyroptosis, the
pro-inflammatory cell-suicide response.
The scientists speculate that the difference in cell death rates between the two methods of infection
is due to the increased efficiency of cell-to-cell transmission. 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. However, in cell-to-cell transmission, the viral DNA fragments
overwhelm cell maintenance, building up until they surpass a threshold and are
detected. This then triggers caspase-1 activation and pyroptosis.
“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,” says senior
author Warner C. Greene, MD, PhD, director
of the Gladstone Institute of Virology and Immunology. “By preventing cell-to-cell transmission, we may
able to block the death pathway and stop the progression from HIV infection to AIDS.”
Other investigators on the study include Kathryn Monroe, Zhiyuan Yang, and Isa Muñoz-Arias from
the Gladstone Institutes, and David Levy from New York University College of Dentistry. Funding was
provided by the National Institutes of Health, National Institute of Allergy and Infectious
Diseases, the UCSF/Robert John Sabo Trust Award, and the Giannini Foundation Postdoctoral
About the Gladstone Institutes
To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound
medical, economic, and social impact—unsolved diseases of the brain, the heart, and the immune system.
Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit
life science research organization that uses visionary science and technology to overcome disease.
Direct line: 415.734.2532
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