In this collaborative mucosal immunity group (CMIG) we propose analysis of the immunological and related virological factor that contribute to intrapartum vertical transmission of HIV. We argue that this analysis represents a uniquely valuable resource for analysis of the role of mucosal immunity and virologic factors in virus transmission. Unlike other transmission scenarios, we will know that exposure will occur, approximately how many of the exposures examined will result in transmission (-15-30%), and when those transmission will occur (50% at birth). Hence, we will be able to isolate those fluids most likely involved in transmission (blood cells, plasma, placenta, cervico-vaginal fluids, amniotic fluid from gastric aspirates) at or near the time (potentially within minutes to hours) of transmission. We will also have access t the newly infected host and the transmitted virus before, during and after the development of the initial immune response. In addition, we will have identical access to materials from exposures that do not result in transmission that will permit us to contrasts both virologic features and protective immune factors. In this component to the CMIG, we will take a multifaceted approach to identify the virologic features which correlate with transmission or failure to transmit. The interrelation of virologic factors and immune response factors will be used to test several alternative hypotheses regarding their biological significance to the instances of transmission and non-transmission observed. To test the hypothesis that virus load and stage of infection of the mother plays a role in transmission, we will determine proviral DNA and viral RNA load in each maternal sample as well as in infant blood. To test the hypothesis that particular virus variants are more likely to be transmitted and to identify the maternal compartments that transmitted viruses are found, we will search for unique features of transmitted virus variants using the newly developed heteroduplex mobility (HMA) and homoduplex tracking assays (HTA), as well as selective nucleotide sequence analysis. We will clone and then use regions of the infant viruses as probes to simultaneously evaluate changes in selected regions of the env and gag structural genes, as well as changes in the vif, vpu, vpr, tat, rev and nef regulatory genes, in each maternal virus compartment. Complete gp160 coding sequences from 10 infant viruses will be completely sequenced. Furthermore, infant viral genomes will be cloned by overlap extension PCR, and expressed, if needed as infectious virus in order to identify virologic and immunologic features correlated with transmission. Our goals of identification of factors contributing to successful mucosal transmission, as well as correlates of the failure to transmit, should provide insight into developing affective intervention strategies.
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| Goulston, C; McFarland, W; Katzenstein, D (1998) Human immunodeficiency virus type 1 RNA shedding in the female genital tract. J Infect Dis 177:1100-3 |
| Goulston, C; Stevens, E; Gallo, D et al. (1996) Human immunodeficiency virus in plasma and genital secretions during the menstrual cycle. J Infect Dis 174:858-61 |
