[CD4 lymphocytes as targets and actors in the pathogenesis of HIV infection--therapeutic implications].
CD4 T lymphocytes play a central role in the pathogenesis of human immunodeficiency virus (HIV) infection. In viremic patients, these cells are direct targets for the virus: HIV multiplies intensely in this subpopulation during the acute phase of the disease and continues to propagate in these same cells during the clinical latency phase. Uninfected CD4 T lymphocytes are also indirectly affected during this second phase: they are activated, become anergic, then disappear by apoptosis, ultimately contributing to CD4 lymphopenia. Our studies have shown that dysfunction of the interleukin-2 system and its receptors largely explain the early immune deficiency seen in viremic patients. Later, blockade of the homeostatic interleukin-7/CD4 loop contributes to rendering this CD4 lymphopenia irreversible. Our studies suggest that the inflammatory reaction which accompanies this infection gives rise to a state of abnormal activation, with receptor desensitization to the main cytokines regulating CD4 lymphocyte functions and numbers. In the few rare patients who manage to control HIV in the absence of any treatment, the CD4 T cell compartment has a very characteristic configuration. We have shown that an extensive subpopulation of "central memory" CD4 T lymphocytes expresses large quantities of the CCR7 homing receptor and that this helps drive these lymphocytes to infected lymph nodes. Also, these "central memory" CD4 T lymphocytes produce large quantities of IL-2, that they use in an autocrine manner, stimulating their self-renewal and ensuring their long-term survival. Our studies have opened the door to cytokine-based immunotherapy and to the development of new drug- and vaccine-based strategies.
Theze
Jacques
J
Unité d'ImmunoGénétique Cellulaire, Centre d'Infectiologie Necker Pasteur, Institut Pasteur, 25/28 rue du Docteur Roux, 75015 Paris. jtheze@pasteur.fr
D000208:Acute Disease; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D019898:Autocrine Communication; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology / Q000821:virology; D020276:HIV Long-Term Survivors; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000502:physiology; D015851:Interleukin-7 / Q000097:blood / Q000502:physiology; D008213:Lymphocyte Activation; D038041:Lymphopoiesis; D054400:Receptors, CCR7 / Q000502:physiology; D014766:Viremia / Q000276:immunology / Q000821:virology
D019380:Anti-HIV Agents; C515370:CCR7 protein, human; C508605:IL7 protein, human; D007376:Interleukin-2; D015851:Interleukin-7; D054400:Receptors, CCR7