A number of theories have been developed to explain how HIV infection results in the destruction or loss of CD4 T-cells. Although many of these studies took place relatively early in the epidemic, the observations are still relevant in explaining the range of mechanisms by which CD4 T-cell death takes place in the body.

Syncytium formation

In a laboratory setting, HIV-infected and uninfected CD4 T-cells can form a clump or syncytium of fused cells which soon die. Strains of HIV found in late infection are more likely to have the ability to cause syncytium formation: the cytokine interleukin-15 (IL-15) may play a role in the transition from non-syncytium inducing (NSI) to syncytium inducing (SI) viral strains.

It is not known whether the clumping of CD4 T-cells is actually important inside the body. It is known, however, that SI strains are able to replicate faster than NSI strains and the actual turnover of virus may be the mechanism killing CD4 T-cells rather than syncytium formation itself

Excessive gp120

During the time when HIV is replicating in CD4 T-cells there is excessive production of HIV proteins which can be released into the bloodstream and act as antigens. Free proteins called gp120 could attach to CD4 molecules on uninfected CD4 T-cells leading to an attack on the cell by antibodies and cytotoxic cells. Possibly, the attachment of gp120 to CD4 also inhibits the function of the CD4 T-cell.

Apoptosis

Normally, all cells can be programmed to die if they need replacing or eliminating. This is called apoptosis. An abnormally large proportion of infected and uninfected CD4 T-cells seem to be programmed for apoptosis in people with HIV infection. The reason is unclear but may involve the attachment of free HIV proteins to CD4 T-cells or due to cell over-activation.

One possibility is that HIV antigens act as 'superantigens' that can activate a larger range of CD4 T-cells than normal and which can cause increased replication of HIV. Changes in cytokine levels, such as increased tumour necrosis factor (TNF) and decreased interleukin-1 (IL-1), may also induce apoptosis. Interleukin-2 (IL-2) may rescue some cells from apoptosis. Interestingly, CD8 T-cells, natural killer cells and B-cells are also prone to apoptosis during HIV infection. However, while apoptosis of T-cells is common, there seems to be no apoptosis of HIV-infected macrophages or monocytes (Goldberg 1999).

Some studies have suggested that apoptosis of infected, resting T-cells can occur following programming which directs the cells home to the lymph nodes (Chen 1999).

Because over-activation of the immune system is likely to play a major role in the increased levels of apoptosis observed in T-cells, as well as aiding increased production of HIV, methods to dampen down immune activation may be beneficial. The use of immune suppressant therapies, such as corticosteroids, may therefore be of benefit in reducing the over-stimulation of the immune system, and CD4 T-cell death seen during chronic HIV infection.

References

Chen JJY et al.The potential importance of HIV-induction of lymphocyte homing to lymph nodes. Int Immunol 11: 1591-1594, 1999.

Goldberg B et al. Apoptosis and HIV infection: T-cells fiddle while the immune system burns. Immunol Lett 70: 5-8, 1999.