Pronounced Acute Immunosuppression in vivo Mediated by HIV Tat Challenge

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 19; pp. 10842 - 10847
• Main Authors: Cohen, Sandra S., Li, Chiang, Ding, Linna, Cao, Yunzhen, Pardee, Arthur B., Shevach, Ethan M., Cohen, David I.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 14.09.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: AIDS Vaccines - metabolism; AIDS/HIV; Animals; Antibodies; Antigens; Biological Sciences; Cells, Cultured; Disease; Dose-Response Relationship, Drug; Fas antigen; Fas Ligand Protein; FasL protein; Flow Cytometry; Gene Products, tat - immunology; Gene Products, tat - metabolism; Gene Products, tat - pharmacology; HIV; HIV infections; HIV Infections - immunology; HIV Infections - metabolism; Human immunodeficiency virus; Humans; Immune Tolerance - physiology; Immunoblotting; Immunology; Immunosuppression; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Monocytes; Proteins; Recombinant Proteins - pharmacology; T lymphocytes; T-Lymphocytes, Helper-Inducer - drug effects; tat Gene Products, Human Immunodeficiency Virus; Tetanus; Vaccination; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.19.10842

HIV infection is accompanied by an early immune dysfunction limiting host control of virus and likely contributing to difficulties in achieving a successful vaccine against HIV. We report here that the HIV Tat protein is strongly immunosuppressive, both immediately after immunization of mice with soluble protein (sTat), and in seroconverting humans, and propose that Tat-induced suppression cripples immune surveillance to HIV infection. We show that macrophages are sensitive to sTat stimulation at concentrations 1,000-fold lower (500 pM) than T cells, and this stimulation is accompanied by the immunosuppressive induction of Fas ligand on the macrophage. T cell proliferative defects induced by sTat in vitro can be completely (at lower concentrations of sTat) or partially (at higher concentrations) reversed by antagonists to Fas/Fas ligand interaction. We further report a method to preserve immunogenicity while inactivating Tat immunosuppression through oxidation, which advances the use of oxidized Tat as a component of an anti-HIV vaccine. These observations define additional methods to study the immunosuppressive functions of sTat that now may be rapidly applied to primary isolates from individuals with differing clinical courses. Our findings have immediate relevance for vaccine development, by describing and supporting a strategy that includes inactivated sTat in a multicomponent, anti-HIV vaccine.