Although, in its final stages, AIDS is a disease of immuno-suppression, a state of general immune activation is characteristic of the lymphoid tissue and blood lymphocytes of an AIDS patient during the whole of the asymptomatic phase of the disease. It is the continual expression of HIV antigens that is the cause of the chronic stimulation of the immune system. This activation is seen in the expression of certain activation markers on both CD4 and CD8 T cells. Under normal conditions, apoptosis is extremely important in the homeostasis of cell numbers that occurs after antigenic stimulation and which leads to the removal of primed lymphocytes to terminate an immune reaction. This homeostasis also avoids autoimmune reactions. But the state of immune activation in the chronically HIV-infected patient may pose a distinct problem since activated cells will be apoptotically eliminated, especially when other infections lead to the production of cytokines that further activate the cells.

Thus one might expect that the T cells of the blood of HIV-infected patients would  be very sensitive to induction of apoptosis in vitro, and this is the case  with both CD4 and CD8 cells (and also B cells and dendritic cells). As many as 50% of freshly isolated peripheral blood lymphocytes from an HIV-infected patient undergo apoptosis when cultured in normal medium but only 2-5% of similar cells from an uninfected patient undergo apoptosis. It is also found that there is additional apoptosis induced by activators such as cytokines in lymphocytes of HIV-infected patients but no such activation-induced apoptosis in the cells of uninfected subjects. As has been stressed already, the actual number of CD4 cells that are HIV-infected in the patient is usually low and induction of sensitivity to apoptosis could be the basis of the by-stander effect in which uninfected CD4 cells also disappear from the circulation of the infected AIDS patient. In fact, the uninfected cells seem to be primed for apoptosis in preference to the infected cells.

Several studies have shown that the degree of CD4 cell apoptosis correlates with the pathological course of the disease:

a) The proportion of CD4 and CD8 T cells that demonstrate spontaneous or T cell receptor- or CD95-mediated apoptosis increases as the infection progresses and the CD4 number falls

b) There is diminished spontaneous apoptosis of T cells in long term non-progressing HIV-infected patients

c) There is elevated spontaneous apoptosis of T cells in patients that progress rapidly to AIDS

d) Apoptosis is observed only in pathogenic lentiviral infections

e) In chimpanzees with high HIV-1 particle number, there is a loss of CD4 cells, immune activation and elevated apoptosis but apoptosis did not occur in the absence of immune activation and CD4 loss

How does this apoptosis occur? Despite much research, we do not yet have the answer but it is known that the CD95 surface antigen is involved. This protein is a member of the tumor necrosis factor receptor (TNFR) family. It spans the plasma membrane and has what is known as a "death domain" in its cytoplasmic region. This domain is involved in signaling the cell to undergo apoptosis when a ligand binds to the extracellular portion of the receptor.  The receptor can signal apoptosis either in an autocrine or paracrine fashion (that is when one cell produces a signal that causes that same cell to commit suicide (autocrine signal) or when another cell produces a signal that causes a different cell to commit suicide (paracrine signal). The ligand that binds to the CD95 protein is the CD95 ligand (CD95L).  Increased CD95 expression is observed in the CD4 and CD8 lymphocytes of HIV-infected patients and by the time that AIDS disease appears the cells are 90% CD95 positive. CD95L expression is also elevated in HIV-infected patients. An important observation made in HIV-infected chimpanzees is that a lower degree of CD4 cell loss correlates with resistance to the onset of the symptoms of AIDS.  This lack of CD4 cell depletion is associated with resistance of the cells to CD95-mediated apoptosis. It should also be noted that CD95L expression is elevated in CD4 cells by infection with HIV or in the presence of HIV proteins such as gp120. This results in these cells killing CD95-expressing cells including other CD4 cells and CD8 cells.

Note: Other members of the TNFR family may be involved and in CD8 cells, apoptosis seems to involve the prototypical TNF-alpha/TNF receptor signaling pathway. In this, binding of gp120 alone to CXCR4 (one of the co-receptors for HIV) on  macrophages causes the expression of TNF while the same binding in CD8 cells causes the expression of TNFR. The interaction of the TNF with the TNFR causes the CD8 cell to commit apoptosis (This is described further in the main HIV  notes). 

Thus there are a number of  ways in which apoptosis can be induced via binding of HIV proteins (or the virus itself) to CD4 antigen or CXCR4 on the surfaces of cells that express these receptors.

Other ways in which HIV-1 infection is thought to lead to apoptosis of CD4 T lymphocytes

1.  Viral gp160 on the surface of an infected cell can bind to CD4 antigen on a neighboring uninfected cell. Both gp120 and gp41 are required. No other genes are needed. Gp160-dependent apoptosis of uninfected CD4 cells involves caspases but CD95 (Fas) surface antigen and TNF receptors are not involved.

2. Tat protein can sensitize cells to apoptosis signaled via CD95, CD4 or TNF receptors. CD95 or T cell receptor signaling are required.

3. Vpr can cause cells to arrest in the G2/M phase of the cell cycle and then to induce apoptosis

4. Vpu sensitizes T cells to CD95-induced apoptosis

For further information see: Gougeon, M-L and Montagnier, L. Programmed cell death as a mechanism of CD4 and CD8 T cell deletion in AIDS. Annals of the New York Academy of Sciences, 887: 199-212, 1999