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    Role of human immunodeficiency virus type 1 accessory genes in mother-infant transmission

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    Author
    Yedavalli, Venkat Sita Rama Krishna
    Issue Date
    1999
    Keywords
    Biology, Microbiology.
    Health Sciences, Medicine and Surgery.
    Advisor
    Ahmad, Nafees
    
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    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    The majority of AIDS cases in children occur as a result of perinatal transmission of HIV-1 at an estimated rate of 30%. However, the molecular mechanisms and viral determinants associated with perinatal transmission are not known, thus making it difficult to develop strategies for prevention and treatment of HIV-1 infection. In this study, we have investigated the role of HIV-1 accessory genes vif, vpr and vpu in maternal-fetal transmission and the kinetics of HIV-1 replication in neonatal blood mononuclear cells. While there was a high degree of conservation of vif, vpr and vpu open reading frames in mother-infant pairs' isolates, the non-transmitting mothers' showed a high frequency of defective vif and vpr open reading frames. The functional domains required for Vif, Vpr and Vpu activity were highly conserved in sequences from transmitting mothers and their infants, but were found to exhibit defects, length polymorphism and substitutions in the conserved motifs of non-transmitting mothers' isolates. There was a low degree of heterogeneity in vif and vpr sequences from transmitting mothers and their infants and non-transmitting mothers. However the non-transmitting mother sequences were less heterogeneous than transmitting mother sequences. The vpu sequences from transmitting mothers and their infants were more heterogeneous than vif and vpr sequences. Phylogenetic analysis of vif, vpr and vpu sequences revealed distinct clusters for each mother-infant pair and non-transmitting mother, indicating that the sequences from same individual or linked individuals were more closer than unrelated individuals. Furthermore, we observed that HIV-1 replicates more efficiently in immature blood lymphocytes and monocytes/macrophages cells compared to mature blood cells, suggesting that increased susceptibility of neonatal cells to productive infection could result in rapid progression to AIDS in children. In addition, there was a difference in the susceptibility of neonatal and adult blood monocytes/macrophages to primary HIV-1 isolates. Taken together, these findings suggest that accessory genes vif, vpr and vpu may play an essential role in HIV-1 transmission from mother to infants and susceptibility of neonatal monocytes/macrophages may be critical for establishing productive infection. These findings may be helpful in the developing better strategies for prevention and treatment of HIV-1 infection in children.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Microbiology and Immunology
    Degree Grantor
    University of Arizona
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