Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. 2010

Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.

We biochemically simulated HIV-1 DNA polymerization in physiological nucleotide pools found in two HIV-1 target cell types: terminally differentiated/non-dividing macrophages and activated/dividing CD4(+) T cells. Quantitative tandem mass spectrometry shows that macrophages harbor 22-320-fold lower dNTP concentrations and a greater disparity between ribonucleoside triphosphate (rNTP) and dNTP concentrations than dividing target cells. A biochemical simulation of HIV-1 reverse transcription revealed that rNTPs are efficiently incorporated into DNA in the macrophage but not in the T cell environment. This implies that HIV-1 incorporates rNTPs during viral replication in macrophages and also predicts that rNTP chain terminators lacking a 3'-OH should inhibit HIV-1 reverse transcription in macrophages. Indeed, 3'-deoxyadenosine inhibits HIV-1 proviral DNA synthesis in human macrophages more efficiently than in CD4(+) T cells. This study reveals that the biochemical landscape of HIV-1 replication in macrophages is unique and that ribonucleoside chain terminators may be a new class of anti-HIV-1 agents specifically targeting viral macrophage infection.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D009711 Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed) Nucleotide
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002853 Chromatography, Liquid Chromatographic techniques in which the mobile phase is a liquid. Liquid Chromatography
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012265 Ribonucleotides Nucleotides in which the purine or pyrimidine base is combined with ribose. (Dorland, 28th ed) Ribonucleoside Phosphates,Ribonucleotide,Phosphates, Ribonucleoside
D015496 CD4-Positive T-Lymphocytes A critical subpopulation of T-lymphocytes involved in the induction of most immunological functions. The HIV virus has selective tropism for the T4 cell which expresses the CD4 phenotypic marker, a receptor for HIV. In fact, the key element in the profound immunosuppression seen in HIV infection is the depletion of this subset of T-lymphocytes. T4 Cells,T4 Lymphocytes,CD4-Positive Lymphocytes,CD4 Positive T Lymphocytes,CD4-Positive Lymphocyte,CD4-Positive T-Lymphocyte,Lymphocyte, CD4-Positive,Lymphocytes, CD4-Positive,T-Lymphocyte, CD4-Positive,T-Lymphocytes, CD4-Positive,T4 Cell,T4 Lymphocyte
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015967 Gene Expression Regulation, Viral Any of the processes by which cytoplasmic factors influence the differential control of gene action in viruses. Regulation of Gene Expression, Viral,Viral Gene Expression Regulation,Regulation, Gene Expression, Viral

Related Publications

Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
July 1991, Proceedings of the National Academy of Sciences of the United States of America,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
February 1996, Biological chemistry Hoppe-Seyler,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
October 1991, The Journal of biological chemistry,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
July 2006, Journal of virology,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
January 2004, Current topics in medicinal chemistry,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
October 1995, The Journal of biological chemistry,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
January 2006, Current pharmaceutical design,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
January 1996, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
April 1993, Molecular pharmacology,
Edward M Kennedy, and Christina Gavegnano, and Laura Nguyen, and Rebecca Slater, and Amanda Lucas, and Emilie Fromentin, and Raymond F Schinazi, and Baek Kim
January 1996, Advances in virus research,
Copied contents to your clipboard!