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. 1990 Apr;87(8):3087–3091. doi: 10.1073/pnas.87.8.3087

Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine.

H Egberink 1, M Borst 1, H Niphuis 1, J Balzarini 1, H Neu 1, H Schellekens 1, E De Clercq 1, M Horzinek 1, M Koolen 1
PMCID: PMC53839  PMID: 2158102

Abstract

The acyclic purine nucleoside analogue 9-(2-phosphonomethoxyethyl)adenine [PMEA; formerly referred to as 9-(2-phosphonylmethoxyethyl)adenine] is a potent and selective inhibitor of human immunodeficiency virus replication in vitro and of Moloney murine sarcoma virus-induced tumor formation in mice. In the latter system PMEA has stronger antiretroviral potency and selectivity than 3'-azido-3'-thymidine (AZT). We have now investigated the effect of the drug in cats infected with the feline immunodeficiency virus (FIV). In vitro, PMEA was found to efficiently block FIV replication in feline thymocytes (50% effective dose, 0.6 microM). When administered to cats at doses of 20, 5, or 2 mg/kg per day, PMEA caused a dose-dependent suppression of FIV replication and virus-specific antibody production. Seropositive field cats with signs of opportunistic infection (gingivitis, stomatitis, and diarrhea) showed clinical improvement during PMEA therapy (5 mg/kg per day) and recurrence of the disease after treatment was discontinued. Thus, FIV infection in cats is an excellent model to test the efficacy of selective anti-human immunodeficiency virus agents in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balzarini J., Naesens L., Herdewijn P., Rosenberg I., Holy A., Pauwels R., Baba M., Johns D. G., De Clercq E. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc Natl Acad Sci U S A. 1989 Jan;86(1):332–336. doi: 10.1073/pnas.86.1.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  3. Brunner D., Pedersen N. C. Infection of peritoneal macrophages in vitro and in vivo with feline immunodeficiency virus. J Virol. 1989 Dec;63(12):5483–5488. doi: 10.1128/jvi.63.12.5483-5488.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De Clercq E., Holý A., Rosenberg I. Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo. Antimicrob Agents Chemother. 1989 Feb;33(2):185–191. doi: 10.1128/aac.33.2.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ellis T. M. Feline respiratory virus carriers in clinically healthy cats. Aust Vet J. 1981 Mar;57(3):115–118. doi: 10.1111/j.1751-0813.1981.tb00471.x. [DOI] [PubMed] [Google Scholar]
  6. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  7. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  8. Gangemi J. D., Cozens R. M., De Clercq E., Balzarini J., Hochkeppel H. K. 9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections. Antimicrob Agents Chemother. 1989 Nov;33(11):1864–1868. doi: 10.1128/aac.33.11.1864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gaskell R. M., Povey R. C. Re-excretion of feline viral rhinotracheitis virus following corticosteroid treatment. Vet Rec. 1973 Aug 18;93(7):204–205. doi: 10.1136/vr.93.7.204. [DOI] [PubMed] [Google Scholar]
  10. Harbour D. A., Williams P. D., Gruffydd-Jones T. J., Burbridge J., Pearson G. R. Isolation of a T-lymphotropic lentivirus from a persistently leucopenic domestic cat. Vet Rec. 1988 Jan 23;122(4):84–86. doi: 10.1136/vr.122.4.84. [DOI] [PubMed] [Google Scholar]
  11. Hoover E. A., Zeidner N. S., Perigo N. A., Quackenbush S. L., Strobel J. D., Hill D. L., Mullins J. I. Feline leukemia virus-induced immunodeficiency syndrome in cats as a model for evaluation of antiretroviral therapy. Intervirology. 1989;30 (Suppl 1):12–25. doi: 10.1159/000150120. [DOI] [PubMed] [Google Scholar]
  12. Ishida T., Washizu T., Toriyabe K., Motoyoshi S., Tomoda I., Pedersen N. C. Feline immunodeficiency virus infection in cats of Japan. J Am Vet Med Assoc. 1989 Jan 15;194(2):221–225. [PubMed] [Google Scholar]
  13. Knowles J. O., Gaskell R. M., Gaskell C. J., Harvey C. E., Lutz H. Prevalence of feline calicivirus, feline leukaemia virus and antibodies to FIV in cats with chronic stomatitis. Vet Rec. 1989 Apr 1;124(13):336–338. doi: 10.1136/vr.124.13.336. [DOI] [PubMed] [Google Scholar]
  14. Naesens L., Balzarini J., Rosenberg I., Holý A., De Clercq E. 9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo. Eur J Clin Microbiol Infect Dis. 1989 Dec;8(12):1043–1047. doi: 10.1007/BF01975167. [DOI] [PubMed] [Google Scholar]
  15. North T. W., North G. L., Pedersen N. C. Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. Antimicrob Agents Chemother. 1989 Jun;33(6):915–919. doi: 10.1128/aac.33.6.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Olmsted R. A., Barnes A. K., Yamamoto J. K., Hirsch V. M., Purcell R. H., Johnson P. R. Molecular cloning of feline immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2448–2452. doi: 10.1073/pnas.86.7.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Olmsted R. A., Hirsch V. M., Purcell R. H., Johnson P. R. Nucleotide sequence analysis of feline immunodeficiency virus: genome organization and relationship to other lentiviruses. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8088–8092. doi: 10.1073/pnas.86.20.8088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pauwels R., Balzarini J., Schols D., Baba M., Desmyter J., Rosenberg I., Holy A., De Clercq E. Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob Agents Chemother. 1988 Jul;32(7):1025–1030. doi: 10.1128/aac.32.7.1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pedersen N. C., Ho E. W., Brown M. L., Yamamoto J. K. Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science. 1987 Feb 13;235(4790):790–793. doi: 10.1126/science.3643650. [DOI] [PubMed] [Google Scholar]
  20. Pedersen N. C., Torten M., Rideout B., Sparger E., Tonachini T., Luciw P. A., Ackley C., Levy N., Yamamoto J. Feline leukemia virus infection as a potentiating cofactor for the primary and secondary stages of experimentally induced feline immunodeficiency virus infection. J Virol. 1990 Feb;64(2):598–606. doi: 10.1128/jvi.64.2.598-606.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Richman D. D., Fischl M. A., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Hirsch M. S. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):192–197. doi: 10.1056/NEJM198707233170402. [DOI] [PubMed] [Google Scholar]
  22. Spaan W. J., Rottier P. J., Horzinek M. C., van der Zeijst B. A. Isolation and identification of virus-specific mRNAs in cells infected with mouse hepatitis virus (MHV-A59). Virology. 1981 Jan 30;108(2):424–434. doi: 10.1016/0042-6822(81)90449-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Talbott R. L., Sparger E. E., Lovelace K. M., Fitch W. M., Pedersen N. C., Luciw P. A., Elder J. H. Nucleotide sequence and genomic organization of feline immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5743–5747. doi: 10.1073/pnas.86.15.5743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tavares L., Roneker C., Postie L., de Noronha F. Testing of nucleoside analogues in cats infected with feline leukemia virus: a model. Intervirology. 1989;30 (Suppl 1):26–35. doi: 10.1159/000150121. [DOI] [PubMed] [Google Scholar]
  25. Yamamoto J. K., Sparger E., Ho E. W., Andersen P. R., O'Connor T. P., Mandell C. P., Lowenstine L., Munn R., Pedersen N. C. Pathogenesis of experimentally induced feline immunodeficiency virus infection in cats. Am J Vet Res. 1988 Aug;49(8):1246–1258. [PubMed] [Google Scholar]
  26. Yarchoan R., Berg G., Brouwers P., Fischl M. A., Spitzer A. R., Wichman A., Grafman J., Thomas R. V., Safai B., Brunetti A. Response of human-immunodeficiency-virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet. 1987 Jan 17;1(8525):132–135. doi: 10.1016/s0140-6736(87)91968-4. [DOI] [PubMed] [Google Scholar]
  27. Yarchoan R., Klecker R. W., Weinhold K. J., Markham P. D., Lyerly H. K., Durack D. T., Gelmann E., Lehrman S. N., Blum R. M., Barry D. W. Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986 Mar 15;1(8481):575–580. doi: 10.1016/s0140-6736(86)92808-4. [DOI] [PubMed] [Google Scholar]

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