Viral and Host Factors Associated with HIV-1 Vertical Transmission and Pathogenesis

Persistent Link:
http://hdl.handle.net/10150/194040
Title:
Viral and Host Factors Associated with HIV-1 Vertical Transmission and Pathogenesis
Author:
Mehta, Roshni
Issue Date:
2008
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 neonates and infants acquire HIV-1 infection through vertical transmission. In addition these HIV-1 infected infants have a higher viral load and progress to AIDS faster than adults, often times more rapidly than their own infected mothers. However, the mechanisms of this differential disease progression are not well understood. Several studies have shown, including work from our laboratory, that it is the transmission of the minor genotype with the R5 phenotype that is involved in transmission. We have also shown that a lower viral heterogeneity may influence vertical transmission. Moreover, we have also shown that there is a differential HIV- influenced at the level of HIV-1 gene expression and not at the level of expression of receptors or coreceptors. Moreover, I have characterized the cellular gene expression profile of uninfected and infected cord monocyte-derived macrophages (MDM) as compared with adult MDMs. Evaluation of these cellular factors identified genes that fell into several classes including transcriptional activators/repressors, cytokines, and matrix metalloproteinases, all of which may be able to influence HIV-1 gene expression. To explain this differential HIV-1 gene expression, I have modulated the level of cellular factors (IL6 and STAT3) using short hairpin RNA (shRNA) technology to determine if these cellular factors were playing a role in an increased HIV-1 replication and gene expression. I found that upon downregulation of these factors, there was a decrease in HIV-1 LTR directed gene expression. Taken together, the results from this dissertation provide new insights into elucidating the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression in neonates and infants. This work which has identified several cellular factors may offer new possibilities for the development of therapeutic strategies to treat pediatric AIDS.1 replication and HIV-1 gene expression in neonatal cells as compared to adult cells. The hypothesis of this dissertation is that viral determinants and cellular factors in neonatal and adult mononuclear cells influence HIV-1 replication and HIV-1 gene expression. In this dissertation I have molecularly characterized the HIV-1 long terminal repeat (LTR) from 6 mother-infant HIV-1 infected pairs, and shown that mutations generated during vertical transmission correlate with HIV-1 gene expression. Furthermore, I have also shown that there was a low degree of viral heterogeneity and a high conservation of critical transcription factor binding sites within the LTR. I have also shown that nuclear extracts from neonatal (cord) mononuclear cells bind with higher efficiencies to HIV-1 LTR as compared to nuclear extracts from adult mononuclear cells. In addition, I have also made strides in trying to elucidate the mechanisms of differential HIV-1 replication and gene expression. I have shown that there is a differential HIV-1 replication in naïve and memory T-lymphocytes from cord vs. adults and this increased HIV-1 replication was
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Immunobiology; 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.titleViral and Host Factors Associated with HIV-1 Vertical Transmission and Pathogenesisen_US
dc.creatorMehta, Roshnien_US
dc.contributor.authorMehta, Roshnien_US
dc.date.issued2008en_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.abstractThe majority of neonates and infants acquire HIV-1 infection through vertical transmission. In addition these HIV-1 infected infants have a higher viral load and progress to AIDS faster than adults, often times more rapidly than their own infected mothers. However, the mechanisms of this differential disease progression are not well understood. Several studies have shown, including work from our laboratory, that it is the transmission of the minor genotype with the R5 phenotype that is involved in transmission. We have also shown that a lower viral heterogeneity may influence vertical transmission. Moreover, we have also shown that there is a differential HIV- influenced at the level of HIV-1 gene expression and not at the level of expression of receptors or coreceptors. Moreover, I have characterized the cellular gene expression profile of uninfected and infected cord monocyte-derived macrophages (MDM) as compared with adult MDMs. Evaluation of these cellular factors identified genes that fell into several classes including transcriptional activators/repressors, cytokines, and matrix metalloproteinases, all of which may be able to influence HIV-1 gene expression. To explain this differential HIV-1 gene expression, I have modulated the level of cellular factors (IL6 and STAT3) using short hairpin RNA (shRNA) technology to determine if these cellular factors were playing a role in an increased HIV-1 replication and gene expression. I found that upon downregulation of these factors, there was a decrease in HIV-1 LTR directed gene expression. Taken together, the results from this dissertation provide new insights into elucidating the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression in neonates and infants. This work which has identified several cellular factors may offer new possibilities for the development of therapeutic strategies to treat pediatric AIDS.1 replication and HIV-1 gene expression in neonatal cells as compared to adult cells. The hypothesis of this dissertation is that viral determinants and cellular factors in neonatal and adult mononuclear cells influence HIV-1 replication and HIV-1 gene expression. In this dissertation I have molecularly characterized the HIV-1 long terminal repeat (LTR) from 6 mother-infant HIV-1 infected pairs, and shown that mutations generated during vertical transmission correlate with HIV-1 gene expression. Furthermore, I have also shown that there was a low degree of viral heterogeneity and a high conservation of critical transcription factor binding sites within the LTR. I have also shown that nuclear extracts from neonatal (cord) mononuclear cells bind with higher efficiencies to HIV-1 LTR as compared to nuclear extracts from adult mononuclear cells. In addition, I have also made strides in trying to elucidate the mechanisms of differential HIV-1 replication and gene expression. I have shown that there is a differential HIV-1 replication in naïve and memory T-lymphocytes from cord vs. adults and this increased HIV-1 replication wasen_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineImmunobiologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorAhmad, Nafeesen_US
dc.contributor.chairAhmad, Nafeesen_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.contributor.committeememberCollins, Jamesen_US
dc.contributor.committeememberSchluter, Samuelen_US
dc.identifier.proquest2582en_US
dc.identifier.oclc752259908en_US
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