INTRODUCTION

Apoptosis has been described as a homeostatic mechanism to limit the expression of activated lymphocytes and may contribute to the elimination of T cells after viral disease resolution.¹ However, it has become evident that accelerated apoptosis, which follows immune system overactivation, plays a prominent role in human immunodeficiency virus (HIV) infection.

The concept was refined by demonstrating that cell death occurs mainly in bystander cells, which are not infected by the virus,⁶ and increased susceptibility to apoptosis correlated with disease progression.⁷ The authors concluded that “chronic activation of the immune system is the primary mechanism for the cell deletion process.”⁷ Furthermore, it was demonstrated that apoptosis is massive during primary infection and involves mitochondria functionality.^8,9 It was then elegantly shown that T cell activation is more closely associated with disease progression than plasma virus burden during HIV infection.¹⁰ In the case of HIV, according to the “autoimmunity” hyperactivation model, the immune system is eventually exhausted.¹¹ For example, during late-stage AIDS, dramatic increases in virus titers are often observed followed by overwhelming infection, which may activate the majority of CD8 effector cells, depleting this HIV-specific subset.¹¹ The fact that CD4 T cell depletion correlates more closely with levels of immune activation than viral load was confirmed during HIV-1 infection and extended to HIV-2 infection.¹² Interestingly, patients with similar CD4 depletion had dramatically different viral loads but strikingly similar levels of immune activation, regardless of whether they were infected by HIV-1 or HIV-2. Another study, the “Amsterdam Cohort,”¹³ focused on the level of CD4 and CD8 T cell activation at different time points after infection before and after documented seroconversion.

In a compelling manuscript,¹⁴ researchers analyzed the importance of immune activation for total body CD4 count in 43 rhesus macaques. It was shown that despite reduced CD4 counts in the blood and reduced CD4:CD8 in the blood and lymph nodes, the total body CD4 counts and the number of proliferating CD4 significantly increased throughout the entire phase of asymptomatic infection. This was due mainly to CD4 increases in the secondary lymphoid organs. Total body CD8 counts and the number of proliferating CD8 increased even more significantly, again due mainly to increases in the secondary lymphoid organs, thus lowering the CD4:CD8 (a reduced CD4:CD8 was already observed in human lymph nodes^15,16; however, this was incorrectly interpreted by the field as the result of a selective CD4 decrease). The context changed during AIDS, due to reduced proliferation and complete exhaustion of thymic function. The authors concluded that a drastically increased turnover in the early stages of HIV infection, driven by a generalized immune activation (with an important bystander component) rather than a homeostatic response to CD4 T cell destruc­tion, is followed by exhaustion of the regenerative capacity of the immune system. In other words, the antigen drives the immune system, which, in turn, activates homeostatic mechanisms to control its expansion, and the whole immune machinery drives at maximum speed until exhaustion.

These data helped substantially in interpreting HIV pathogenesis and may have relevant clinical implications. In this chapter, we will discuss chronic immune activation; the exaggerated, precocious apoptosis of T cell subsets; CD95-induced apoptosis and pathogenic implications; and alternative therapy options within the context of highly active antiretroviral therapy (HAART) that include cytokines and cytostatic drugs (i.e., hydroxyurea, mycophenolic acid, cyclosporin).