The AIDS epidemic involves increasing numbers of children, most of whom are infected with the human immunodeficiency virus type 1 (HIV-1) by their mothers. Presently, no effective therapy exists to prevent maternal transmission of HIV-1. The overall goal of this proposal is to develop a primate model for pediatric AIDS, using the simian immunodeficiency virus (SIV). Because maternal SIV infection occurs only rarely, if ever, in infected pregnant rhesus monkeys, we propose to use ultrasound-guided inoculation of fetal compartments.
The specific aims are to: 1. Define the minimal infectious dose of SIV(mac251) required for fetal infection following ultrasound-guided inoculation of amniotic fluid. Our data indicate that cell-free SIV given by this route in the 3rd trimester infects the fetus successfully. Virus entry is thought to occur via skin or mucous membrane contact when the fetus swallows SIV+ amniotic fluid. A similar mode of infection may occur naturally during birth. We plan to find an SIV inoculum that will reliably result in infected, live-born offspring. 2. Define the pathogenicity of SIV(mac251) when the fetus is infected at various time points during gestation. Will early prenatal infection lead to a more aggressive course of disease? Does the incidence of nervous system involvement rise or is tissue distribution of SIV altered as fetuses are infected at earlier time points? Does fetal infection during the first trimester lead to abortion? 3. Define the immune response to SIV i rhesus monkeys infected in utero at different times. Can fetuses infected late in gestation mount cytotoxic T-cell responses against SIV gag-expressing cells? Do they develop neutralizing antibodies? Does early in utero exposure to SIV lead to tolerance? 4. Test whether antiviral drugs administered to pregnant rhesus monkeys can protect their fetuses against subsequent intrauterine SIV challenge. Efficacy, toxicity and teratogenicity will be monitored in parallel. 5. Compare the pathogenicity of SIV if the route of infection is altered, or if infection occurs through infected maternal peripheral blood mononuclear cells. To mimic maternal virus passage across the placenta, which results in SIV entry into the fetal circulation, we plan to use ultrasound-guided transabdominal injection of the umbilical vain and compare the outcome with amniotic fluid infection. Is transplacental antiviral drug prophylaxis equally effective against cell-free versus cell-associated virus? The proposed work is highly significant for establishing a primate model system for fetal and neonatal lentiviral infection. Because it emphasizes high infection rates, such a model system will be cost effective for evaluating viral pathogenesis during ontogeny as well as prophylaxis. Our proposed experiments may yield important information for planning clinical trials aimed at preventing maternal HIV-1 transmission.
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