Immune Destruction of T Cells. Stem Cell Arrest. Immune Disorders

While the production of HIV genomes and proteins can directly lead to cell death, infected T cells can also be killed by other immune cells. In particular, cytotoxic T cells (typically bearing CD8 surface markers) kill cells expressing foreign antigens on their surface. This physiological response protects the host by eliminating infected cells. Cells expressing the viral envelope glycoprotein on their surface can be killed by cytotoxic T cells specific for that antigen. Moreover, CD4⁺ cells can be targeted for killing even without being infected.

This event can occur if the CD4⁺ surface molecule binds, internalizes, and processes a gpl20 envelope subunit that has dissociated from the transmembrane subunit (gp41) of the virion or an infected cell. When the processed gpl20 is cycled back to the cell surface, it can, under some circumstances, be recognized as foreign by a cytotoxic T cell. Whether this mechanism results in a substantial amount of cell killing in infected persons remains to be determined.

Antibodies also participate in marking cells for immune destruction by a process called antibody- dependent cellular cytotoxicity. Anti-HIV antibodies, generated as part of the normal immune response, bind to infected cells expressing HIV envelope proteins and mark them for killing by effector cells such as NK cells. The effector cells typically recognize antibody-coated cells by an interaction between the Fc domain of the antibody and an Fc receptor on the effector cell.

Stem Cell Arrest. While there are many different ways that HIV can lead to the death of CD4⁺ T cells, it seems unlikely that cell killing alone can completely explain the CD4⁺ T cell depletion seen in AIDS. Only a small percentage of the circulating mononuclear cells (i.e., T cells and monocytes/macrophages) in infected individuals show signs of active infection. Thus, at any given time, relatively few cells seem to be subjected to the pathological effect of HIV replication. This finding supports theories proposing that HIV commonly exists in a latent state in the cell; that is, viral RNA and proteins are not made.

Another reason T cell death cannot completely explain the profound loss of T cells is that the body has the potential for replenishing its supply of lymphocytes. This fact has prompted theories suggesting that HIV might directly infect the stem cells responsible for restoring the immune system, or that infection of some immune cells could lead to a loss of growth factors responsible for signaling regeneration of lymphocytes. Conclusive evidence for such theories is currently lacking, although HIV infection of precursor T cells in culture has been reported.

Immune Disorders.In addition to cell killing, HIV induces more subtle changes in infected cells. For example, infected T cells might not produce adequate amounts of cytokines, which are important for the proper functioning of other immune cells. Cell surface molecules are also affected by HIV. A common finding among T cells infected in culture is a decreased level of expression of the CD4 surface antigen. This HIV- induced modulation of the CD4 molecule is seen most frequently in established cell lines (tumor cells that grow indefinitely in culture), but can also occur in primary blood lymphocytes (normal cells that have a limited life span in culture).

The mechanism of this decrease in surface CD4 expression is not known, but preliminary evidence suggests that intracellular complexing of the CD4 molecule with the envelope glycoprotein can occur during transit to the cell surface. Other studies have also demonstrated decreased levels of CD4 mRNA in some cell lines. The physiological consequences of the down- regulation of CD4, regardless of the mechanism, is unknown, but it is likely that it could affect intercellular communication. Finally, there have been reports of down-regulation of other surface molecules (e.g., the interleukin-2 receptor) in some infected cell lines. This event could also contribute to immune dysfunction.

Monocytes and macrophages are also frequently infected by HIV and therefore could suffer direct pathological consequences. Some virus isolates cause marked cytopathological effects in monocytes and macrophages, although, in general, there seem to be fewer effects among infected macrophages than among infected T cells. However, the increased viability of infected macrophages might allow them to maintain prolonged virus production.

Reduced cytokine production, as observed in infected T cells, has also been reported in infected macrophages. This defect might explain why HIV- infected individuals commonly suffer from infections such as tuberculosis and toxoplasmosis, in which activated macrophages are the primary effector cells.