RESUMEN
Simple affordable interventions are needed to reduce vertical human immunodeficiency virus (HIV) transmission in developing countries. The efficacy of 2 low doses (4 mg/kg, subcutaneously) or 1 high dose (30 mg/kg, subcutaneously) of the reverse-transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) to protect newborn macaques against simian immunodeficiency virus (SIV) infection was investigated. Thirteen newborn macaques were inoculated orally with virulent SIVmac251. The 4 placebo-treated animals (group A) became persistently infected. Groups B and C (n=4 in each group) received 2 4-mg/kg doses of PMPA, either 4 h before and 20 h after (group B) or 1 and 25 h after SIV inoculation (group C). One animal (group D) received a single 30-mg/kg dose of PMPA 1 h after SIV inoculation. Despite evidence of an initial transient infection, 3 group B animals, 2 group C animals, and the group D animal were SIV negative and seronegative at ages 19-23 months. Immune activation with recall antigens or pharmacologic immunosuppression with corticosteroids failed to reactivate viral replication. These data suggest that 1 or 2 doses of PMPA may protect human newborns against intrapartum HIV infection.
Asunto(s)
Adenina/análogos & derivados , Adenina/administración & dosificación , Fármacos Anti-VIH/administración & dosificación , Organofosfonatos , Compuestos Organofosforados/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Adenina/efectos adversos , Animales , Fármacos Anti-VIH/efectos adversos , Anticuerpos Antivirales/sangre , ADN Viral/sangre , Humanos , Activación de Linfocitos , Macaca mulatta , Compuestos Organofosforados/efectos adversos , Provirus , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Virus de la Inmunodeficiencia de los Simios/fisiología , TenofovirRESUMEN
Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-¿2-(R)-(phosphonomethoxy)propyladenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA-treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.
Asunto(s)
Adenina/análogos & derivados , Antivirales/farmacología , Organofosfonatos , Compuestos Organofosforados/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Adenina/administración & dosificación , Adenina/farmacología , Administración Oral , Animales , Animales Recién Nacidos , Antivirales/administración & dosificación , Macaca mulatta , Compuestos Organofosforados/administración & dosificación , Proyectos de Investigación , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , TenofovirRESUMEN
Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study disease pathogenesis and to develop intervention strategies aimed at delaying disease. In the present study, we demonstrate that very early events of infection greatly determine the ultimate disease course, as short-term antiviral drug administration during the initial viremia stage significantly delayed the onset of AIDS. Fourteen newborn macaques were inoculated orally with uncloned, highly virulent SIVmac251. The four untreated control animals showed persistently high virus levels and poor antiviral immune responses; they developed fatal immunodeficiency within 15 weeks. In contrast, SIV-infected newborn macaques which were started on 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) treatment at 5 days of age and continued for either 14 or 60 days showed reduced virus levels and enhanced antiviral immune responses. This short-term PMPA treatment did not induce detectable emergence of SIV mutants with reduced in vitro susceptibility to PMPA. Although viremia increased in most animals after PMPA treatment was withdrawn, all animals remained disease-free for at least 6 months. Our data suggest that short-term treatment with a potent antiviral drug regimen during the initial viremia will significantly prolong AIDS-free survival for HIV-infected infants and adults.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/administración & dosificación , Organofosfonatos , Compuestos Organofosforados/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Adenina/administración & dosificación , Animales , Animales Recién Nacidos , Humanos , Inyecciones Subcutáneas , Macaca mulatta , Tenofovir , Factores de TiempoRESUMEN
BACKGROUND: Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is considered to be a useful model of human pediatric HIV infection. OBJECTIVE: To investigate whether short-term 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) administration can protect newborn rhesus macaques against perinatal SIV infection. DESIGN AND METHODS: Eight newborn macaques were inoculated orally with highly virulent SIVmac within the first 3 days of life. Four of these animals were untreated controls. The other four animals were given one dose of PMPA (30 mg/kg subcutaneously) 4 h before oral SIV inoculation, and were then given a second and final dose of PMPA 24 h later. RESULTS: All four untreated control animals were persistently SIV-positive within 2 weeks after virus inoculation. In contrast, no virus could be detected in the four animals that received two doses of PMPA; these animals were seronegative and healthy at 10 months. CONCLUSIONS: Two doses of PMPA prevented SIV infection of newborn macaques. Our data suggest that short-term administration of PMPA to HIV-infected pregnant women at the onset of labor and to their newborns after delivery may reduce the rate of intrapartum HIV transmission.