MOLECULAR MECHANISMS OF HIV-1 INFECTION: ENTRY, POST-ENTRY, AND GENE EXPRESSION

Persistent Link:
http://hdl.handle.net/10150/194409
Title:
MOLECULAR MECHANISMS OF HIV-1 INFECTION: ENTRY, POST-ENTRY, AND GENE EXPRESSION
Author:
RAMAKRISHNAN, RAJESH
Issue Date:
2005
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:
In the last two decades, a great deal of progress has been made in understanding the molecular biology of HIV-1. However, critical aspects of HIV-1 pathogenesis in infected infants remain poorly understood. The majority of AIDS cases in infants occur as a result of vertical transmission of HIV-1, which occurs at a rate of more than 30%. Moreover, HIV-1 infected infants have a higher level of viremia and progress more rapidly to AIDS than infected adults. My hypothesis is that specific molecular and biological properties of HIV-1 and its differential interaction with hosts (neonates and adults) influence transmission, infection, and disease progression. The projects making up this dissertation investigate the molecular mechanisms of HIV-1 vertical transmission, HIV-1 infection in neonatal target cells at levels of entry and post-entry events, and gene expression, and feasibility studies of synthetic molecules that can be used as anti-HIV-1 agents. The env gp41, rev and Rev-responsive element (RRE) were characterized from HIV-1 isolates involved in perinatal transmission. The data indicate that open reading frames and functional domains of env gp41, rev and stem-loop structure of RRE were highly conserved in isolates from mothers and their infants. Furthermore, the mechanisms of HIV-1 infection in neonatal (cord) and adult mononuclear cells were investigated. It was found that HIV-1 replicated better in cord blood lymphocytes and monocytes/macrophages than its adult counterparts, with a more profound difference seen in monocytes/macrophages. This difference in HIV-1 replication kinetics was not influenced either at level of entry (CD4, CCR5 and CXCR4 expression) or early post-entry events (reverse transcription and translocation of HIV-1 DNA into the nucleus) but at the level of HIV-1 gene expression. The biological activity of Gal-Cer and its analogs, and glycolipid conjugates as anti-HIV-1 agents was evaluated. Gal-Cer and its analogs incorporated onto liposomes, and glycolipid conjugates inhibited HIV-1 infection by binding to gp120, suggesting that these agents can be developed as drug delivery vehicles to prevent HIV-1 infection. Results obtained from this dissertation provide new insights into the molecular mechanisms of HIV-1 vertical transmission and pediatric infection, which may be helpful in developing new preventive and therapeutic strategies.
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Microbiology & Immunology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Ahmad, Nafees

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMOLECULAR MECHANISMS OF HIV-1 INFECTION: ENTRY, POST-ENTRY, AND GENE EXPRESSIONen_US
dc.creatorRAMAKRISHNAN, RAJESHen_US
dc.contributor.authorRAMAKRISHNAN, RAJESHen_US
dc.date.issued2005en_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.abstractIn the last two decades, a great deal of progress has been made in understanding the molecular biology of HIV-1. However, critical aspects of HIV-1 pathogenesis in infected infants remain poorly understood. The majority of AIDS cases in infants occur as a result of vertical transmission of HIV-1, which occurs at a rate of more than 30%. Moreover, HIV-1 infected infants have a higher level of viremia and progress more rapidly to AIDS than infected adults. My hypothesis is that specific molecular and biological properties of HIV-1 and its differential interaction with hosts (neonates and adults) influence transmission, infection, and disease progression. The projects making up this dissertation investigate the molecular mechanisms of HIV-1 vertical transmission, HIV-1 infection in neonatal target cells at levels of entry and post-entry events, and gene expression, and feasibility studies of synthetic molecules that can be used as anti-HIV-1 agents. The env gp41, rev and Rev-responsive element (RRE) were characterized from HIV-1 isolates involved in perinatal transmission. The data indicate that open reading frames and functional domains of env gp41, rev and stem-loop structure of RRE were highly conserved in isolates from mothers and their infants. Furthermore, the mechanisms of HIV-1 infection in neonatal (cord) and adult mononuclear cells were investigated. It was found that HIV-1 replicated better in cord blood lymphocytes and monocytes/macrophages than its adult counterparts, with a more profound difference seen in monocytes/macrophages. This difference in HIV-1 replication kinetics was not influenced either at level of entry (CD4, CCR5 and CXCR4 expression) or early post-entry events (reverse transcription and translocation of HIV-1 DNA into the nucleus) but at the level of HIV-1 gene expression. The biological activity of Gal-Cer and its analogs, and glycolipid conjugates as anti-HIV-1 agents was evaluated. Gal-Cer and its analogs incorporated onto liposomes, and glycolipid conjugates inhibited HIV-1 infection by binding to gp120, suggesting that these agents can be developed as drug delivery vehicles to prevent HIV-1 infection. Results obtained from this dissertation provide new insights into the molecular mechanisms of HIV-1 vertical transmission and pediatric infection, which may be helpful in developing new preventive and therapeutic strategies.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_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.chairAhmad, Nafeesen_US
dc.contributor.committeememberAhmad, Nafeesen_US
dc.contributor.committeememberMarchalonis, John J.en_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.contributor.committeememberFriedman, Richarden_US
dc.contributor.committeememberSchluter, Samuel L.en_US
dc.identifier.proquest1180en_US
dc.identifier.oclc659747454en_US
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