INTRODUCTION
Infection with human immunodeficiency virus type 1 (HIV-1) causes a decline in CD4+ T cells leading to acquired immunodeficiency syndrome (AIDS).1-2 Although mathematical modeling estimates show that the majority of infected cells die with a half-life of about 2 days,3-5 the number of infected cells is reported to be approximately constant.4 This implies that there is the production and destruction of large numbers of infected cells each day.
Although it is not clear what ultimately leads to the progressive and selective depletion of CD4+ T cells, it may be inferred that the destruction of these cells exceeds their replacement (discussed in detail in Chapter 19).Our understanding of the molecular mechanism of HIV-1 replication and viral protein functions has advanced tremendously. However, key elements of the pathogenesis of HIV-1 infection are not completely defined. The mode of viral killing by acute infection has been a focus of numerous studies but remains highly controversial. A strongly favored hypothesis is that HIV-1 induces apoptosis in infected cells as well as bystander cells (discussed in Chapters 13-16, 19, and 21). However, considerable evidence also indicates that HIV cytopathicity does not require the presence or the upregulation of cellular apoptotic factors. Furthermore, the majority of dying infected cells do not display the hallmarks of apoptosis.6-12 In fact, it was suggested that direct viral killing could occur via a nonapoptotic/necrotic pathway.11,12
Another unresolved issue related to the mode of death is whether HIV-1 cytopathicity occurs in uninfected bystander cells. This could occur by syncytia formation, triggering of surface receptors such as CD4, cytokines, or other toxic influences.13-15 Contradictory data were reported regarding direct versus indirect viral killing mainly because many studies examined a mixed population of infected and uninfected cells, which prevents the precise measurement of virally induced apoptosis.
Moreover, cell death in vivo may result from normal homeostatic death mechanisms of activated T cells, infected or not.16,17 This might explain apparent bystander killing in vivo18,19 as discussed in Chapter 13. Accumulating evidence indicates that direct single-cell killing of HIV-1 predominates in peripheral blood mononuclear cells (PBMCs) from most patients and accounts for the majority of cell death in infected cultures.20-22 In experimental tissue culture infections, bystander death is not evident.11,12 There are even newly described mechanisms of “programmed” necrosis that can be triggered by cytokines such as tumor necrosis factor (TNF). This chapter focuses on the mode of death in direct single-cell killing induced by HIV-1 rather than indirect death caused by viral infection. We will discuss a nonapoptotic/necrotic mode of cell death during acute HIV-1 infection and present some of the experimental data that argue against viral killing via apoptosis. We will also review possible mechanisms that could contribute to necrotic cell death induced by HIV-1 infection.