CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause?

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

“…Immune activation has been demonstrated to play a critical role in HIV disease progression [1][2][3][4][5][6][7][8][9][10][11][12][13][14], possibly through the induction of activation-induced cell death (AICD) of bystander non-infected cells [1,43]. We have also shown here that IL-7Ra expression inversely correlates with CD4 + T cell apoptosis, and that the level of apoptosis, particularly in the memory T cell subset, is significantly altered in groups with varied IL7Ra expression.…”

“…Although many correlates have been identified that may influence the rate of HIV progression, including immune activation, and the disruption of T cell homeostasis, a complete understanding of the mechanisms of CD4 + T cell decline remains elusive [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Cytokines that signal through the common gamma chain, such as IL-2, IL-4, IL-7, and IL-15, are some of the main mediators of T cell homeostasis [15][16][17][18][19][20][21].…”

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

“…Previously proposed mechanisms for HIV1-mediated CD4 þ T cells cell death induction include the killing of productively infected CD4 þ T cells caused either by direct viral cytopathic effects or by antiviral cytotoxic T lymphocytes; 5-7 the killing of bystander CD4 þ T cells caused, in the absence of productive infection, by the binding or the entry of viral proteins released by infected cells or proteins present on or inside the viral particles; 1,2,8-10 and the activation-induced cell death of various uninfected immune cells, including CD4 þ T cells, caused by excessive, ongoing immune activation induced by high persistent viral antigen load. 1,2,4,8,9 An important implication of our findings is that each of these viral-or immune-mediated CD4 þ T-cell killing mechanisms might not only contribute to CD4 þ T-cell loss through a simple cumulative process; rather the extent of cell death occurring in vivo during HIV1 infection, whatever its causal mechanism and the nature of the dying cells, may by itself allow, above a given threshold and in the presence of a sufficient amount of HIV1 particles, the induction of an additional, synergic pathogenic mechanism causing further bystander CD4 þ T-cell killing. Our findings may thus help conciliate the often opposed views on the respective contributions of viral load and immune activation to progression toward AIDS, 4 since they provide a framework suggesting that viral production, viral cytopathic effects, immunemediated cell killing, and activation-induced cell death might all contribute to the induction of a common amplification process of CD4 þ T-cell depletion, which requires the presence of both HIV1 particles and dying cells.…”

“…The mechanisms by which HIV1 induces CD4 þ T-cell death, however, remain a critical unresolved issue of AIDS pathogenesis. [1][2][3][4] At least three major, nonmutually exclusive mechanisms have been proposed. The first one is the killing of productively infected CD4 þ T cells, caused either by direct viral cytopathic effects or by antiviral cytotoxic CD8 þ T lymphocytes.…”

“…1,2,[8][9][10] The third proposed mechanism is excessive, ongoing immune activation caused by a high, persistent viral antigen load and leading to the activation-induced death of various uninfected immune cells, including CD4 þ T cells. 1,2,4,8,9 Evidence for the involvement of indirect mechanisms of CD4 þ T-cell killing has been provided by the identification in vivo [11][12][13][14][15][16] and ex vivo [17][18][19] of increased number of dying, uninfected immune cells, including CD4 þ T cells, both in HIV1-infected persons and in non-human primate models of pathogenic simian immunodeficiency virus (SIV) infection, that are closely related to HIV. An important question is whether HIV1 may only cause death in activated, cycling CD4 þ T cells, or also in unstimulated noncycling CD4 þ T cells, which represent at any given time point the vast majority of the CD4 þ T cells in HIV1-infected persons.…”