JAIDS Journal of Acquired Immune Deficiency Syndromes, 2000
Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV... more Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.
Duchenne muscular dystrophy and Becker muscular dystrophy (BMD) are caused by mutations in the dy... more Duchenne muscular dystrophy and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. Although many in-frame deletions in the dystrophin gene lead to mild cases of BMD, truncations within the N-terminal actin-binding domain (ABD1) typically decrease dystrophin expression and lead to more severe cases of BMD. Because of the large reduction in protein expression, the functional capacity of dystrophin proteins deleted for subportions of ABD1 has been difficult to ascertain. ABD1 contains three actin-binding sequences designated ABS1-3. In the present study, we examined the pathophysiological effects of in-frame actin-binding sequence deletions in the context of a highly functional microdystrophin (DeltaR4-R23/DeltaCT). We delivered microdystrophins into the tibialis anterior muscles of 2-day-old dystrophin-deficient mdx mice using recombinant adeno-associated viral vectors. Muscles expressing microdystrophin with an intact ABD1 displayed normal morphology and specific force generation and were partially protected from contraction-induced injury when evaluated at 4 months of age. In contrast, muscles expressing microdystrophins lacking ABS2 and 3 or ABS3 alone developed significantly lower levels of specific force and were highly susceptible to contraction-induced injury. Microdystrophins with deletions within ABD1 were also less able to protect myofibers from degeneration than was a microdystrophin with the complete ABD1. We conclude that an intact ABD1 is required to support normal contractile properties of skeletal muscle and to protect against myofiber necrosis.
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2000
Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV... more Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.
Duchenne muscular dystrophy and Becker muscular dystrophy (BMD) are caused by mutations in the dy... more Duchenne muscular dystrophy and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. Although many in-frame deletions in the dystrophin gene lead to mild cases of BMD, truncations within the N-terminal actin-binding domain (ABD1) typically decrease dystrophin expression and lead to more severe cases of BMD. Because of the large reduction in protein expression, the functional capacity of dystrophin proteins deleted for subportions of ABD1 has been difficult to ascertain. ABD1 contains three actin-binding sequences designated ABS1-3. In the present study, we examined the pathophysiological effects of in-frame actin-binding sequence deletions in the context of a highly functional microdystrophin (DeltaR4-R23/DeltaCT). We delivered microdystrophins into the tibialis anterior muscles of 2-day-old dystrophin-deficient mdx mice using recombinant adeno-associated viral vectors. Muscles expressing microdystrophin with an intact ABD1 displayed normal morphology and specific force generation and were partially protected from contraction-induced injury when evaluated at 4 months of age. In contrast, muscles expressing microdystrophins lacking ABS2 and 3 or ABS3 alone developed significantly lower levels of specific force and were highly susceptible to contraction-induced injury. Microdystrophins with deletions within ABD1 were also less able to protect myofibers from degeneration than was a microdystrophin with the complete ABD1. We conclude that an intact ABD1 is required to support normal contractile properties of skeletal muscle and to protect against myofiber necrosis.
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