HIV, cytokines and programmed cell death. A subtle interplay.
HIV infection is marked by the progressive destruction of the CD4 T lymphocyte subset, an essential component of the immune system and a vital source of cytokines required for differentiation of natural killer (NK) and gamma delta T cells, for maturation of B lymphocytes into plasmocytes, and for differentiation of CD8+ T cells into virus-specific cytotoxic T lymphocytes. CD4 T lymphocytes are also a source of chemokines which control migration of lymphocytes to the site of infection and which also inhibit HIV entry into CD4-expressing targets. Continuous production of viral proteins leads to an unbalanced immune activation and to the triggering of apoptotic programs, turning mononuclear cells, including CD4 T cells, CD8 T cells and APC, into effectors of apoptosis, leading to fratricidal destruction of healthy uninfected cells expressing the death receptors. Inappropriate PCD is also responsible for the disappearance of T helper cells primed for type-1 cytokine synthesis, thus contributing to the lack of survival factors which could prevent spontaneous lymphocyte apoptosis. Under potent anti-retroviral therapies, a significant decrease in spontaneous, TCR- and CD95-induced lymphocyte apoptosis is observed, concomitant with a partial quantitative and qualitative restoration of the immune system in treated patients. However, owing to the suppressive effect of anti-retroviral drugs on physiological apoptosis, these therapies are associated with alteration of TNF-alpha-regulated T cell homeostasis, leading to an accumulation in the blood of T cells primed for TNF-alpha synthesis, and contributing to the development of a new syndrome associated with these treatments, the lipodystrophy syndrome.
Gougeon
M L
ML
Unité d'Oncologie Virale and CNRS URA 1930, Département SIDA et Rétrovirus, Institut Pasteur, 28 Rue du Dr. Roux 75724 Paris, France. mlgougeo@pasteur.fr
Ledru
E
E
Naora
H
H
Bocchino
M
M
Lecoeur
H
H
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D008060:Lipodystrophy / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019380:Anti-HIV Agents; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha