Efforts to control the dissemination of HIV through the world's population is compounded by the emergence of HIV infection and disease in the heterosexual population. Vertical transmission of HIV from infected mother to developing fetus is estimated to occur at a rate of 30-50%. A suitable animal model is desperately needed to identify strategies effective in blocking this mode of transmission. We propose to utilize our extensive experience with the SIV: macaque for AIDS to fulfill this need by examining the ability of 2 well-characterized isolates of SIV that vary in virulence, SIV/DeltaB670 and SlVmac clone BK-28, to cross the placenta and cause neonatal disease in 3 species of macaques known to be susceptible to SIV-induced disease as adults. We reason that, although the best isolate is theoretically one that can do both, virulent strains may promote abortion rather than infected neonates. Moreover, a comparison of the effects on the developing fetus of isolates that induce either chronic or acute disease in adult monkeys may provide information useful to our understanding of pathogenic mechanism(s) employed in fetal infection and disease. The incidence of transplacental infection and the nature of fetal disease will be directly compared in three species of macaque (rhesus, cynomolgus, and pigtail) to identify the species best suited for model development. Experiments involving nonhuman primates are labor-intensive and expensive; a higher incidence of transmission means fewer animals per experimental group. In year 1, fetal and neonatal disease induced by the 2 virus isolates will be determined in fetuses inoculated directly by umbilical vein cannulation, caesarian delivered, and hand-reared. This experiment will not only allow characterization of fetal disease but also provide information regarding the optimal virus strain for subsequent studies. Timed mated pregnant females from each species will be inoculated in year 2 during midgestation to identify the optimal species for transplacental infection. The effects of vaginal versus caesarian delivery on perinatal infection will be determined in year 3. A systematic examination of the dissemination of virus from the placenta to the fetal tissues and the pathobiology of fetal disease will be performed in Year 4 in fetuses infected at monthly intervals during gestation. SIV-induced infection and disease will be thoroughly monitored virologically, pathologically, and immunologically by a team of investigators experienced in SIV research using well-documented methodologies. These experiments will elucidate the nature of fetal disease, identify factors responsible for transplacental infection, and provide a working model for maternal-fetal transmission desperately needed for testing drugs and vaccine regima effective in prevention.
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