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

Abstract

The acyclic purine nucleoside analogue 9-(2-phosphonomethoxyethyl)adenine [PMEA; formerly referred to as 9-(2-phosphonylmethoxyethyl)adenineJ 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 immunodefciency virus (FlY). In vitro, PMEA was found to efficiently block FIV replication in feline thymocytes (50% effective dose, 0.6 ,uM).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 exceflent model to test the efficacy of selective anti-human immunodeficiency virus agents in vivo.

Efficacy of antiviral chemotherapy for retrovirus-infected cats

“…62 Several studies have investigated the efficacy of adefovir in cats either experimentally or naturally infected with FIV. 10,[63][64][65][66][67] Some of these studies have reported some efficacy, but also severe side effects, mainly in the form of non-regenerative anaemia. More recently, adefovir was used in FIV-infected cats in a 6 week placebo-controlled, double-blind clinical trial; 10 cats received the drug (10 mg/kg SC twice weekly) and 10 cats received placebo.…”

Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients

“…Data on the pharmacokinetics of adefovir in a number of animal species are available, including mice (16), rats (8,19), cats (13), and monkeys (3,4,10). Plasma adefovir concentrations generally declined in a biexponential manner following intravenous administration, with apparent terminal half-lives ranging from ϳ0.1 h in mice to 2.0 h in rhesus monkeys.…”

Comparative Anti-Retrovirus and Anti-Hepadnavirus Activity of Three Different Classes of Nucleoside Phosphonate Derivatives

“…It inhibits HIV-induced cytopathicity in MT-4 and ATH8 cells, and HIV-specific antigen expression in MT-4 and H9 cells at a concentration (0.4-7 J..lM) that is well below the toxicity threshold for the host cells (40-144 J..lM) (Pauwels et al, 1988;Balzarini et al, 1989Balzarini et al, , 1991. PMEA also proved effective in inhibiting Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblast cells at 1 J..lM, feline immunodeficiency virus (FIV) replication in Crandell feline kidney cells and in feline peripheral blood lymphocytes at 0.3-1.3 and 0.06-0.1 J..lM, respectively, and simian immunodeficiency virus (SIV)-induced giant cell formation and cytopathic effect in HUT-78 and MT-4 cells at 4-17 J..lM (Balzarini et al, 1989(Balzarini et al, , 1991Egberink et al, 1990;Hartmann et sl., 1993Hartmann et sl., , 1994. Moreover, PMEA showed potent and selective anti-retrovirus activity in several animal models including MSV infection in newborn NMRI mice (Balzarini et al, 1989(Balzarini et al, , 1991, FIV infection in cats (Hartmann et al, 1993) and SIV infection in rhesus monkeys (Egberink et al, 1990;Tsai et al, 1994).…”

“…PMEA also proved effective in inhibiting Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblast cells at 1 J..lM, feline immunodeficiency virus (FIV) replication in Crandell feline kidney cells and in feline peripheral blood lymphocytes at 0.3-1.3 and 0.06-0.1 J..lM, respectively, and simian immunodeficiency virus (SIV)-induced giant cell formation and cytopathic effect in HUT-78 and MT-4 cells at 4-17 J..lM (Balzarini et al, 1989(Balzarini et al, , 1991Egberink et al, 1990;Hartmann et sl., 1993Hartmann et sl., , 1994. Moreover, PMEA showed potent and selective anti-retrovirus activity in several animal models including MSV infection in newborn NMRI mice (Balzarini et al, 1989(Balzarini et al, , 1991, FIV infection in cats (Hartmann et al, 1993) and SIV infection in rhesus monkeys (Egberink et al, 1990;Tsai et al, 1994). Interestingly, PMEA has also shown activity against human and duck hepatitis B virus in human HB611 and Hep G2 2.2.15 cells and in primary duck hepatocyte cultures at 0.2 and 1.2 J..lM, respectively (Heijtink et al, 1993;Yokota et al, 1994).…”