CD40 ligand dysregulation in HIV infection: HIV glycoprotein 120 inhibits signaling cascades upstream of CD40 ligand transcription.
IL-12 production and up-regulation of CD40 ligand (CD40L) expression are impaired in the PBMC of HIV-infected donors, and exogenous CD40L rescues IL-12 production by such cells. In this study, we implicate dysregulation of CD40L expression in the IL-12 defect associated with HIV by demonstrating that induction of CD40L expression by anti-CD3/CD28 stimulation was directly correlated with the IL-12 productive capacity of PBMC. Further, we demonstrate marked decreases in the induction of CD40L protein and mRNA following anti-CD3/CD28 stimulation in HIV-infected donors compared with uninfected donors, with a tight association between these two levels. Inhibition of CD40L up-regulation was selective, as induction of CD69 or OX40 was not as severely affected. Increased instability of CD40L mRNA did not constitute a major mechanism in CD40L dysregulation, thus suggesting a potential defect in the signaling cascades upstream of transcription. The mechanisms by which HIV infection affects the induction of CD40L expression appear to involve HIV gp120-mediated engagement of CD4. Indeed, anti-CD4 mAb or inactivated HIV virions that harbor a conformationally intact gp120 significantly inhibited CD40L up-regulation at both the protein and mRNA levels. This inhibition was due to the native, virion-associated gp120, as coculture with soluble CD4 or heat treatment of inactivated HIV abolished their effect. These in vitro models mirror the CD40L defect seen in cells from HIV-infected donors and thus provide a suitable model to investigate HIV-induced CD40L dysregulation. Clear elucidation of mechanism(s) may well lead to the development of novel immunotherapeutic approaches to HIV infection.
Zhang
Rui
R
Divisions of Molecular Immunology and Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Fichtenbaum
Carl J
CJ
Hildeman
David A
DA
Lifson
Jeffrey D
JD
Chougnet
Claire
C
D000328:Adult; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation; D015536:Down-Regulation / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006679:HIV Seropositivity / Q000276:immunology; D006207:Half-Life; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D023201:CD40 Ligand; D018664:Interleukin-12; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate