Pediatric AIDS is one of the fastest growing aspects of the AIDS pandemic. In addition, there is a more rapid development of HIV disease in a majority of infected infants compared with infected adults. The pathogenesis of pediatric AIDS may be partially explained by relative immaturity of the immune system in early infancy. However, the molecular mechanisms of HIV-1 pathogenesis and disease progression in infants are not clearly understood, making it difficult to design new and effective strategies for treatment and prevention of HIV-1 infection in infants. Our hypothesis is that the specific molecular and biological properties of HIV-1 and unique interactions of HIV-1 with immature hosts? mononuclear cells are critical determinants of HIV-1 pathogenesis and disease progression in infected infants. In the proposed studies, we will determine the molecular and biological properties of HIV-1 in 30 infected infants during the course of infection and disease progression and study the interactions of HIV-1 with immature hosts? cells in terms of viral replication kinetics and its possible mechanisms.
The specific aims are to: 1) To characterize HIV-1 quasispecies in infected infants during the course of infection and disease progression, 2) To determine the biological properties and coreceptors utilization of HIV-1 from infected infants during the course of infection and disease progression, and 3) To study the interactions of HIV-1 with immature hosts? mononuclear cells, including kinetics of HIV-1 replication, entry and post entry events, cell activation and proliferation, and HIV-1 gene expression. To achieve these objectives, the experiments will be designed by using 30 HIV-1 infected infants and their follow-up samples every 6 months for 4 years. 1) HIV-1 genotypes will be identified and characterized in the regions of env gp120, vi[ and vpr from infants? PBMC DNA and plasma virions? RNA by PCR amplification followed by nucleotide sequencing and in-depth analyses by computer programs. 2) The biological properties will be determined by evaluating the replication efficiency, cell tropism, cytopathic effects and coreceptor utilization of HIV-1 isolates from infected infants and chimeras from the regions of env gp120, vif and vpr during the course of infection and disease progression. 3) The interactions of HIV-1 with immature hosts? mononuclear cell will be determined by infecting immature (cord) and adult blood lymphocytes and monocytes/macrophages from 20 donors each with several HIV-1 primary isolates and evaluating the kinetics of HIV-1 replication, entry and post entry events, cell activation and proliferation, and HIV-1 gene expression. The insights generated by these studies may contribute to a better understanding of the molecular mechanisms of HIV-1 pathogenesis and accelerated disease progression in infected infants compared with infected adults. These results may be helpful in developing new and better strategies for the treatment and prevention of HIV-1 infection in infants and children.
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