In the context of HIV-driven, prolonged overactivation of the immune system, ultimately leading to AIDS, Rethi and colleagues have identified key components able to support both life and death of immune-competent T cells.
Rethi and colleagues have shown that Fas, increasingly expressed during T-cell depletion in lymphopenic conditions such as HIV-1 infection, and known to transmit apoptotic (death) signals to repeatedly activated antigen-specific T cells, also plays a role in stimulating T-cell expansion through costimulatory signals in suboptimally activated T cells. They also found that the cytokine IL-7, which is elevated in response to T-cell depletion, increases the efficacy of Fas in inducing proliferation of these cells. In other words, while letting overactivated cells die, the same molecules allow suboptimally activated cells to live and expand, reiterating the process of life and death of the immune system endlessly.
These findings add another piece to the puzzle of HIV pathogenesis, and fit within the current, prevailing interpretation that prolonged immune overactivation induced by HIV during the course of chronic infection exhausts the immune system and leads to AIDS. Initially, it was shown that chronic high levels of immune activation accompany pathogenic HIV/simian immunodeficiency virus (SIV) infection, and the consequent induction of apoptosis during continued, chronic activation of the immune system deletes reactive T cells, resulting in progression to AIDS.1,2 This concept was supported by the finding that apoptosis does not mainly occur in HIV-infected cells as first suspected, but rather in bystander cells that are not infected by the virus.3 The increased susceptibility of these bystander cells to apoptosis was shown to correlate with disease progression,4 leading to the conclusion that chronic activation of the immune system is the primary mechanism for cell depletion. The immune system is eventually exhausted by long-term HIV-1 infection.5 This explains why markers of T-cell activation are more closely associated with disease progression than is plasma viral load during HIV infection,6 and CD4 T-cell depletion correlates more closely with levels of immune activation than with viral load during both HIV-1 and HIV-2 infection.7 The nonhuman primate model provided the most elegant, although indirect, evidence that chronic hyperactivation of the immune system is key to HIV disease progression and AIDS: despite persistently high viral loads and massive initial loss of CD4 memory T cells in the lamina propria of the gut, SIV infection in sooty mangabeys is not pathogenic, but rather is characterized by limited immune activation and low bystander immunopathology.8 This is in stark contrast to rhesus macaques, in which persistent SIV replication and resultant high viral loads are associated with high levels of immune activation and progression to AIDS. The reduced response by the sooty mangabey immune system to chronic immune stimulation explains the lack of pathogenic effects despite high viral loads similar to those seen in infected macaques.9
The findings of Rethi and colleagues improve upon the current knowledge of hyperactivation-mediated immune deficiency: while previous literature mainly explains how immune hyperactivation induces immune deficiency, the present manuscript addresses the question of how immune deficiency (or at least one aspect of it, T-cell depletion) leads to hyperactivation, by rendering a subset of T cells more prone to proliferation. The complex interplay between hyperactivation and resultant immune deficiency and, now, between immune deficiency and immune hyperactivation, is becoming increasingly clear, completing the vicious cycle that leads from HIV infection to AIDS.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■