Uninfected CD4 T-cells ‘eat themselves’ when they contact HIV proteins

CD4 T-cells that are not infected with HIV can be killed by contact with the virus’ envelope protein, according to a cell culture study published in the August edition of The Journal of Clinical Investigation. The French investigators demonstrate that the viral protein attaches to the CXCR4 receptor on the T-cell’s surface, which stimulates the cell to commit suicide through a process called ‘autophagy’ or ‘self-eating’.

The loss of CD4 T-cells in HIV-positive patients causes a gradual reduction in the ability of the immune system to fight infections, and without treatment, leads to AIDS. Although infection of CD4 T-cells with HIV is known to cause cell death, cells that are not infected with the virus can also be killed by HIV. These include ‘naïve’ T-cells that have not been exposed to any disease-causing organisms and cannot be infected with HIV. How HIV kills these cells without infecting them is unclear.

To better understand the mechanisms behind the death of uninfected cells, investigators from Montpellier and Villejuif carried out a series of experiments in the test tube using cells that express HIV’s envelope protein. They discovered that this protein attaches to the CXCR4 receptor on the surface of uninfected CD4 T-cells, triggering them to start a process of suicide by increasing the rate of autophagy.

Autophagy is a normal process that cells use to recycle damaged or infected components, by breaking parts of the cell down and re-using the molecules. This can help the cell to survive starvation, old age or infection with a virus. However, the rate of autophagy can be turned up during some infections and in times of stress, with very high rates leading to the cell digesting all of its components and literally ‘eating itself’ to death. Autophagy is distinct from to the other type of programmed cell death called ‘apoptosis’.

The French researchers found that introducing cells with the envelope protein on their surface to CD4 T-cells caused the T-cells to commit suicide via autophagy. They recognised this by observing an increase in the number of ‘vacuoles’ in the cells under the electron microscope. Vacuoles are membrane-bound pockets in the cell where cellular components are broken down.

However, when they repeated their experiment with control cells that did not express HIV’s envelope protein, there was no up-regulation of autophagy.

What’s more, they discovered that the process was blocked by a drug that prevents the envelope protein from binding to CXCR4, but it still went ahead when they used cells with defective versions of the CD4 receptor. This indicated that the CXCR4 receptor was key to stimulating autophagy in the uninfected cells.

Since HIV-infected cells express HIV’s proteins on their surface, the researchers believe that autophagy could be the process by which infected cells lead to the death of uninfected cells, particularly in the lymph nodes where CD4 T-cell death is known to occur, and where infected and uninfected cells come into contact.

Since it involved the CXCR4 receptor, it could also explain why patients with HIV that preferentially uses this receptor have more rapid falls in CD4 cell count, often in the later stages of disease.

In an accompanying commentary article, Beth Levine and Donald Sodora of the University of Texas write, “the HIV envelope glycoprotein induces CXCR4-dependent autophagy of uninfected lymphocytes”.

However, they point out that these cell-based experiments may not necessarily reflect the situation in patients with HIV. “Further work will be needed to determine whether the HIV envelope glycoprotein mediates autophagy-dependent cell death in bystander CXCR4-expressing CD4⁺ lymphocytes in HIV-infected patients and the relative contribution of this process to the progressive decline in numbers of CD4⁺ T cells in patients with AIDS,” they add.

The French study found that autophagy can trigger subsequent apoptosis in uninfected cells that were exposed to HIV proteins. However, the interaction between these two types of cell death is complex and poorly understood.

The study also identified a number of protein molecules that are necessary for autophagy to occur, which could be blocked with drugs and ‘small-interfering ribonucleic acid’ (siRNA) techniques. These molecules may eventually point the way towards new areas for drug development to prevent cell death in HIV-positive patients

Further studies are required to determine whether the CCR5 co-receptor, which is used by most strains of HIV, is also involved in cell death of uninfected cells. There is also uncertainty surrounding whether the envelope proteins can stimulate autophagy when they are found on the surface of the HIV particle, or whether they only trigger autophagy when they are on the surface of infected human cells.