       Document 0408
 DOCN  M9640408
 TI    T-lymphocytes from AIDS patients are unable to synthesize
       ribonucleotides de novo in response to mitogenic stimulation. Impaired
       pyrimidine responses are already evident at early stages of HIV-1
       infection.
 DT    9604
 AU    Bofil M; Fairbanks LD; Ruckemann K; Lipman M; Simmonds HA; Academic
       Department of Clinical Immunology, Royal Free Hospital; School of
       Medicine, London, United Kingdom.
 SO    J Biol Chem. 1995 Dec 15;270(50):29690-7. Unique Identifier : AIDSLINE
       MED/96102014
 AB    Proliferative defects have been reported at the level of DNA synthesis,
       even in T-lymphocytes from asymptomatic human immunodeficiency virus
       type-1+ (HIV-1+) patients. Since purine and pyrimidine ribonucleotide
       availability is crucial for proliferation, we compared the ability of
       HIV-1- and HIV-1+ T-lymphocytes (> 95% CD4+ and CD8+) to activate de
       novo biosynthetic and salvage pathways following phytohemagglutinin
       stimulation using 14C-labeled precursors. The striking abnormality
       already detectable in asymptomatic patients' cells was the impaired
       ability of CTP, UDP-Glc, and UTP pools to expand over 72 h (44-70% of
       control), although ATP and GTP pools and responses were normal. In
       symptomatic patients, resting T-cells showed markedly reduced pyrimidine
       pools (53-74% of control) with no change following activation.
       Relatively normal ATP, GTP, and NAD pools masked the same impaired
       response of de novo synthesis to activation, with ATP and GTP being
       reduced by 50% at 48 h. Purine salvage was more active than the control
       in unstimulated HIV-1+ cells. This impaired de novo synthesis in HIV-1+
       T-lymphocytes severely restricts the availability of ribonucleotides for
       vital growth-related activities such as membrane expansion and strand
       break repair as well as DNA and RNA synthesis. The data indicate that
       resting T-lymphocytes from symptomatic patients survive through enhanced
       salvage, but the stimulation induces metabolic cell death, and provide
       an explanation for the activation-associated lymphocyte death seen in
       HIV-1+ T-lymphocytes.
 DE    Acquired Immunodeficiency Syndrome/*BLOOD/*IMMUNOLOGY  Carbon
       Radioisotopes  Cells, Cultured  Chromatography, High Pressure
       Liquid/METHODS  Comparative Study  Human  HIV
       Infections/BLOOD/IMMUNOLOGY  HIV Seropositivity/*BLOOD/*IMMUNOLOGY
       Kinetics  *Lymphocyte Transformation  Purine Nucleotides/BLOOD/ISOLATION
       & PURIF  Purines/BLOOD/ISOLATION & PURIF  Pyrimidine
       Nucleotides/BLOOD/ISOLATION & PURIF  Pyrimidines/BLOOD/ISOLATION & PURIF
       Radioisotope Dilution Technique  Reference Values
       Ribonucleotides/*BLOOD/ISOLATION & PURIF  Support, Non-U.S. Gov't
       T-Lymphocytes/DRUG EFFECTS/*IMMUNOLOGY/*METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

