Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo

Mycophenolic acid, a selective inhibitor of the de novo synthesis of guanosine nucleotides in T and B lymphocytes, has been proposed to inhibit human immunodeficiency virus (HIV) replication in vitro by depleting the substrate (guanosine nucleotides) for reverse transcriptase. Here we show that mycophenolic acid induced apoptosis and cell death in a large proportion of activated CD4+ T cells, thus indicating that it may inhibit HIV infection in vitro by both virological mechanisms and immunological mechanisms (depletion of the pool of activated CD4+ T lymphocytes). Administration of mycophenolate mophetil, the ester derivate of mycophenolic acid, to HIV-infected subjects treated with anti-retroviral therapy and with undetectable viremia resulted in the reduction of the number of dividing CD4+ and CD8+ T cells and in the inhibition of virus isolation from purified CD4+ T-cell populations. Based on these results, the potential use of mycophenolate mophetil in the treatment of HIV infection deserves further investigation in controlled clinical trials.

[1]  Steven G. Deeks,et al.  Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans , 1999, Nature Medicine.

[2]  J Witek,et al.  Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. , 1999, JAMA.

[3]  H. Mitsuya,et al.  Anti-human immunodeficiency virus type 1 activity of hydroxyurea in combination with 2',3'-dideoxynucleosides. , 1994, Molecular pharmacology.

[4]  J. Lisziewicz,et al.  Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy , 1999, Nature Medicine.

[5]  J N Weinstein,et al.  Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. , 1994, Science.

[6]  Alan S. Perelson,et al.  Decay characteristics of HIV-1-infected compartments during combination therapy , 1997, Nature.

[7]  J. Kahn,et al.  HIV-1 protease inhibitors. A review for clinicians. , 1997 .

[8]  A. Allison,et al.  Lymphocyte‐Selective Cytostatic and Immunosuppressive Effects of Mycophenolic Acid in Vitro: Role of Deoxyguanosine Nucleotide Depletion , 1991, Scandinavian journal of immunology.

[9]  A. Allison,et al.  Bone marrow dysfunction in irradiated, cytomegalovirus-infected mice. , 1991 .

[10]  D. Richman,et al.  Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. , 1999, Science.

[11]  P. Vernazza,et al.  A placebo‐controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection , 1998 .

[12]  M A Fischl,et al.  A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[13]  R Brookmeyer,et al.  Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. , 1997, Science.

[14]  D. Cantrell,et al.  The interleukin-2 T-cell system: a new cell growth model. , 1984, Science.

[15]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[16]  E. Wieschaus,et al.  bottleneck acts as a regulator of the microfilament network governing cellularization of the Drosophila embryo , 1993, Cell.

[17]  A. Perelson,et al.  Target cell availability and the successful suppression of HIV by hydroxyurea and didanosine , 1998, AIDS.

[18]  P. Halloran,et al.  Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. , 1997, Transplantation.

[19]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[20]  C. Flexner.  HIV-protease inhibitors. , 1998, The New England journal of medicine.

[21]  A. Perelson,et al.  Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. , 1999, The New England journal of medicine.

[22]  D. Green,et al.  Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl , 1995, The Journal of experimental medicine.

[23]  R. Siliciano,et al.  Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection , 1997, Nature.

[24]  T V Perneger,et al.  Time of initiation of antiretroviral therapy: impact on HIV-1 viraemia , 2000, AIDS.

[25]  A. Allison,et al.  Lymphocyte‐Selective Antiproliferative and Immunosuppressive Effects of Mycophenolic Acid in Mice , 1991, Scandinavian journal of immunology.

[26]  C. A. Macken,et al.  Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. , 1999, The New England journal of medicine.

[27]  L. McQuay,et al.  Dilution assay statistics , 1994, Journal of clinical microbiology.

[28]  D. Richman,et al.  Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. , 1997, Science.

[29]  M. Zupancic,et al.  Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. , 1997, Science.

[30]  P Fauchald,et al.  PLACEBO-CONTROLLED STUDY OF MYCOPHENOLATE MOFETIL COMBINED WITH CYCLOSPORINE AND CORTICOSTEROIDS FOR PREVENTION OF ACUTE REJECTION , 1995 .

[31]  A. Allison,et al.  Mechanisms of Action of Mycophenolic Acid , 1993, Annals of the New York Academy of Sciences.

[32]  G. Pantaleo,et al.  Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M A Nowak,et al.  Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. , 1999 .

[35]  P. Schnyder,et al.  Limited CD4+ T-cell renewal in early HIV-1 infection: Effect of highly active antiretroviral therapy , 1998, Nature Medicine.

[36]  R. Hogg,et al.  Antiretroviral treatment in 1998 , 1998, The Lancet.

[37]  M. Hellerstein,et al.  Measurement of T-cell kinetics: recent methodologic advances. , 1999, Immunology today.

[38]  C. Boucher,et al.  Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Levy,et al.  Polymerase substrate depletion: a novel strategy for inhibiting the replication of the human immunodeficiency virus. , 1995, Virology.

[40]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[41]  Jerome A. Zack,et al.  HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure , 1990, Cell.

[42]  H. Schuitemaker,et al.  In vitro replication kinetics of human immunodeficiency virus type 1 (HIV-1) variants in relation to virus load in long-term survivors of HIV-1 infection. , 1998, The Journal of infectious diseases.

[43]  G. Pantaleo.  How immune-based interventions can change HIV therapy , 1997, Nature Medicine.

[44]  H. Crissman,et al.  TOTO and YOYO: new very bright fluorochromes for DNA content analyses by flow cytometry. , 1994, Cytometry.