Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy.
Defective immunological function of cells of the macrophage lineage contributes considerably to the pathogenesis of HIV-1 infection. Impairment of phagocytosis of opportunistic pathogens such as Mycobacterium avium complex (MAC), Pneumocystis carinii, Toxoplasma gondii or Candida albicans by peripheral blood monocytes, tissue macrophages and monocyte-derived macrophages following in vivo and in vitro HIV-1 infection is well documented. The development of opportunistic infections due to these pathogens in HIV-infected individuals at late stages of disease is attributed to defective monocyte/macrophage function. The mechanisms whereby HIV-1 impairs phagocytosis are not well known. A number of phagocytic receptors normally mediate engulfment of specific opportunistic pathogens by cells of macrophage lineage; distinct mechanisms are triggered by pathogen-receptor binding to promote cytoskeletal rearrangements and engulfment. This review focuses on the signalling events occurring during Fcgamma receptor- and complement receptor-mediated phagocytosis, and considers the mechanisms by which HIV-1 inhibits those signalling events. Since macrophage function is enhanced by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma), the use of these immunomodulators is of potential interest as adjunctive immunotherapy in immunosuppressed individuals. In this review we present examples of clinical applications of GM-CSF and IFN-gamma therapy for the treatment of opportunistic infections in HIV-infected individuals receiving antiretroviral drugs.
Kedzierska
Katherine
K
AIDS Pathogenesis Research Unit, Macfarlane Burnet Institute for Medical Research and Public Health, Cnr Punt and Commercials Rds, Prahran, Melbourne, VIC 3181, Australia.
Azzam
Rula
R
Ellery
Philip
P
Mak
Johnson
J
Jaworowski
Anthony
A
Crowe
Suzanne M
SM
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D016207:Cytokines / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D011951:Receptors, Complement / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction
D000276:Adjuvants, Immunologic; D016207:Cytokines; D011951:Receptors, Complement; D017452:Receptors, IgG; D011994:Recombinant Proteins; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor