Phosphonylmethoxyalkyl purine and pyrimidine derivatives for treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS.
Murine acquired immunodeficiency syndrome (MAIDS) was induced in C57BL/6 mice following infection with the LP-BM5 retrovirus complex. Infected mice developed splenomegaly, lymphadenopathy and loss of B- and T-cell functions 100 days after virus inoculation. Mice with AIDS were highly susceptible to opportunistic murine cytomegalovirus (MCMV) and herpes simplex virus (HSV-1) infections. The therapeutic activities of two phosphonylmethoxyalkyl derivatives, 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and (S)-1-(3-hydroxy-2-phosphonylmethoxy-propyl)cytosine (HPMPC), were evaluated in MAIDS immunosuppressed mice infected with MCMV or HSV-1. MCMV infection resulted in extensive viral replication in lung, liver and spleen and death occurred five to twelve days post-infection. Treatment with either HPMPC or ganciclovir (DHPG) reduced mortality and viral replication in target organs; however, HPMPC was as effective as DHPG at one-fifth the DHPG dose. Moreover, when a single dose (100 mg/kg) of HPMPC was administered 24 h prior to MCMV infection, it suppressed virus replication at seven and 14 days post-infection, thus resulting in a significant prolongation of life. PMEA was effective against opportunistic HSV-1 infections, but appeared to be less effective than HPMPC against MCMV infections. These results indicate that MAIDS can be used as a model for evaluating antivirals in an immunocompromised host, and suggest that both PMEA and HPMPC may be useful in the treatment of opportunistic CMV and HSV-1 infections.
De Castro
L M
LM
University of South Carolina School of Medicine, Columbia 29208.
Kern
E R
ER
De Clercq
E
E
Ghaffar
A
A
Mayer
E P
EP
Vogt
P E
PE
Gangemi
J D
JD
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D000077404:Cidofovir; D003586:Cytomegalovirus Infections / Q000150:complications / Q000188:drug therapy*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D006561:Herpes Simplex / Q000150:complications / Q000188:drug therapy*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000150:complications*; D009894:Opportunistic Infections / Q000150:complications / Q000188:drug therapy*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use*
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C053001:adefovir; D003596:Cytosine; D000225:Adenine; D000077404:Cidofovir; D015774:Ganciclovir