INTRODUCTION
CD4+ T lymphocyte loss is one of the hallmarks of human immunodeficiency virus (HIV) infection. Because the percentage of T cells undergoing apoptosis is dramatically increased during HIV infection, it may not seem surprising that CD4+ T cells are progressively lost during HIV infection.
There is no consensus, however, on the mechanisms behind increased T cell apoptosis in HIV infection and on the reason why HIV induces an instant loss of CD4+ T cells, whereas CD8+ T cell numbers decline only at late stages of infection. Even though our insights into the different effects of HIV on the immune system have improved during the last decades, many questions remain.Ameisen and Capron1 were the first to propose that CD4+ T cell loss in HIV infection might be due to inappropriate induction of programmed T cell death. They proposed that HIV primes CD4+ T cells to a state in which they become sensitive to T cell apoptosis upon further stimulation. Factors proposed to be involved in HIV-induced inappropriate apoptosis may include direct cyto- pathicity of HIV in productively infected CD4+ T cells and apoptosis of CD4+ T cells via CD4 cross-linking by viral proteins. Later, it was argued that CD4+ T cells are eventually lost in HIV infection, because the immune system gets exhausted by continuously trying to replenish the CD4+ T cell pool,2 whereas others argued that the key problem in HIV infection is interference with T cell renewal, because HIV induces increased apoptosis in the thymus.3-5 In contrast, we and others proposed that apoptosis in HIV infection is a natural result of increased immune activation induced by the virus and that it is this state of chronic immune activation that leads to the progressive loss of CD4+ T cells in HIV infection.6,7 In this chapter, the strengths and weaknesses of the different explanations for increased T cell apoptosis and its relation to CD4+ T cell loss during HIV infection are reviewed.