Molecular Mechanism of HIV-1 Infection: Role of Viral and Host Determinants

Persistent Link:
http://hdl.handle.net/10150/194906
Title:
Molecular Mechanism of HIV-1 Infection: Role of Viral and Host Determinants
Author:
Sundaravaradan, Vasudha
Issue Date:
2006
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:
Most neonates and infants acquire HIV-1 infection as a result of mother-to-infant (vertical) transmission and are infected with the minor genotype with macrophage-tropic (R5) phenotype of the mother. Several studies suggest that infected infants have a higher viral load and develop AIDS more rapidly than infected adults, but the mechanisms of this differential HIV-1 infection are not known. The hypothesis of my dissertation is that viral determinants and differential cellular gene expression profiles influence differential HIV-1 replication and disease progression seen in neonates vs. adults. This work includes characterization of viral determinants, including reverse transcriptase (RT) and envelope gp120, and host determinants, including cellular transcription factors and cytokines that may be associated with differential HIV-1 replication in infants and adults. The characterization of HIV-1 RT gene from five mother-infant pairs following vertical transmission revealed a low degree of viral heterogeneity and a high conservation of intact open reading frames comprising functional domains and CTL epitopes. Biological characterization of HIV-1 subtype C envelope gp120 from infected patients from India was performed by constructing chimeras with HIV-1 subtype B. Infection of cell lines and primary cells with chimeric subtype C/B virus showed that the subtype C env gp120 from patients contributed to an increased rate of virus entry, which correlated with higher replication efficiencies and virus production in subtype C env chimeras compared with subtype B env chimeras and subtype B primary isolates. Higher level of viremia with subtype C infection compared with subtype B may be responsible for its rapid disease progression and spread. The mechanisms of HIV-1 replication in neonatal and adult cells was determined and found that differential HIV-1 replication in neonatal and adult cells is influenced at the level of HIV-1 gene expression. Evaluation of cellular gene expression profile of neonatal and adult mononuclear cells performed by microarray analysis identified several factors, including transcription factors, cytokines and matrix metalloproteinases that may be associated with increased HIV-1 gene expression and replication in neonates and infants. Taken together, these results provide new insights into the understanding of mecahnsims of HIV-1 vertical transmission, pathogenesis and disease progression in infected neonates and infants.
Type:
text; Electronic Dissertation
Keywords:
HIV; infant; transmission; host; factors; subtypes
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Microbiology & Immunology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Ahmad, Nafees
Committee Chair:
Ahmad, Nafees

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMolecular Mechanism of HIV-1 Infection: Role of Viral and Host Determinantsen_US
dc.creatorSundaravaradan, Vasudhaen_US
dc.contributor.authorSundaravaradan, Vasudhaen_US
dc.date.issued2006en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.abstractMost neonates and infants acquire HIV-1 infection as a result of mother-to-infant (vertical) transmission and are infected with the minor genotype with macrophage-tropic (R5) phenotype of the mother. Several studies suggest that infected infants have a higher viral load and develop AIDS more rapidly than infected adults, but the mechanisms of this differential HIV-1 infection are not known. The hypothesis of my dissertation is that viral determinants and differential cellular gene expression profiles influence differential HIV-1 replication and disease progression seen in neonates vs. adults. This work includes characterization of viral determinants, including reverse transcriptase (RT) and envelope gp120, and host determinants, including cellular transcription factors and cytokines that may be associated with differential HIV-1 replication in infants and adults. The characterization of HIV-1 RT gene from five mother-infant pairs following vertical transmission revealed a low degree of viral heterogeneity and a high conservation of intact open reading frames comprising functional domains and CTL epitopes. Biological characterization of HIV-1 subtype C envelope gp120 from infected patients from India was performed by constructing chimeras with HIV-1 subtype B. Infection of cell lines and primary cells with chimeric subtype C/B virus showed that the subtype C env gp120 from patients contributed to an increased rate of virus entry, which correlated with higher replication efficiencies and virus production in subtype C env chimeras compared with subtype B env chimeras and subtype B primary isolates. Higher level of viremia with subtype C infection compared with subtype B may be responsible for its rapid disease progression and spread. The mechanisms of HIV-1 replication in neonatal and adult cells was determined and found that differential HIV-1 replication in neonatal and adult cells is influenced at the level of HIV-1 gene expression. Evaluation of cellular gene expression profile of neonatal and adult mononuclear cells performed by microarray analysis identified several factors, including transcription factors, cytokines and matrix metalloproteinases that may be associated with increased HIV-1 gene expression and replication in neonates and infants. Taken together, these results provide new insights into the understanding of mecahnsims of HIV-1 vertical transmission, pathogenesis and disease progression in infected neonates and infants.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectHIVen_US
dc.subjectinfanten_US
dc.subjecttransmissionen_US
dc.subjecthosten_US
dc.subjectfactorsen_US
dc.subjectsubtypesen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMicrobiology & Immunologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorAhmad, Nafeesen_US
dc.contributor.chairAhmad, Nafeesen_US
dc.contributor.committeememberMarchalonis, John J.en_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.contributor.committeememberSchluter, Samuel F.en_US
dc.contributor.committeememberCollins, James K.en_US
dc.identifier.proquest1685en_US
dc.identifier.oclc137356741en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.