In order to develop strategies to interrupt maternal-fetal transmission our goals are to define the """"""""timing"""""""" of maternal fetal transmission as in utero vs. intrapartum using """"""""state of the art"""""""" and relate maternal risk factors to the route of transmission and to define viral and immunological factors of primary infection in the infant associated with both the timing of infection the time to onset of symptoms and the clearance of virus in infants with """"""""transient"""""""" infection. In a prospective study of HIV (+) pregnant women/infants we will explore our hypothesis that both in utero/intrapartum transmission occur as defined by the presence or absence of HIV virus in the infant at birth and that maternal immune mechanisms including the absence of autologous neutralizing antibody will contribute to development of virus with expanded cell tropism, an increased virus load and the emergence of immune escape virus variants that will transmit to the infant. These factors and placental leaks in the maternal fetal barrier, may be relevant to intrauterine transmission whereas local factors presence of virus or absence of HIV IgA antibody in the genital tract at delivery may be important intrapartum transmission. The timing of infection (fetal or neonatal) may be critical to the potential occurrence of accelerated HIV induced (apoptosis) resulting in early T cell dysfunction and early symptoms. This combined with virological factors (virus load, genotype and phenotype) and immune response of neonates may contribute to the infant's prognosis including the clearance of the virus.
The Specific Aims are-to assess the maternal virus burden (quantitive PCR, culture + ICDP24AG) virus cellular tropism, autologous neutralizing antibody and cervical HIV-IGA and HIV-1 secretion at the time of delivery in relation to the risk of in utero/intrapartum transmission. By molecular genetic analysis of maternal/infant and """"""""neutralization antibody escape virus, we will assess whether immune escape variants are passed to the infant. Placentas will be evaluated for inflammation an cofactors. We will assess the sensitivity and specificity of our definition of in utero vs. intrapartum transmission based on detection of HIV virus (PCR/culture/ICPZ4AG) at birth and the virus load/genotype and phenotype and number of apoptotic cells sequentially in infants an correlate this with the onset of symptoms and outcome. These studies will provide essential information to develop strategies of interruption of maternal- fetal transmission including immune therapy antivirals and vaccines.
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