Molecular Mechanisms of HIV-1 Infection: Viral and Host Determinants in Transmission and Pathogenesis

HIV-1 vertical transmission is the predominant cause of AIDS in children. In addition, HIV-1 infected infants have a higher viral load and progress to AIDS more rapidly than infected adults. However, the molecular mechanisms of HIV-1 vertical transmission and pathogenesis are not known. Work performed in this laboratory has shown transmission of minor genotypes with R5 phenotypes, more heterogeneity associated with transmission and a higher replication and gene expression of HIV-1 in neonatal than adult cells. In this dissertation, I have made advancements by characterizing the HIV-1 gag nucleocapsid gene, that plays a pivotal role in HIV-1 lifecycle, from six mother-infant pairs and found that there was a low degree of viral heterogeneity and a high conservation of functional domains for biological activity and CTL response. With respect to differential mechanisms of HIV-1 infection in neonatal vs. adults cells, 468 HIV-1 integration sites were characterized in the T-lymphocytes and monocyte-derived-macrophages from 5 donors of infant and adult blood. Several functional classes of genes were identified by gene ontology to be over represented, including genes for cellular components, maintenance of intracellular environment, enzyme regulation, cellular metabolism, catalytic activity and cation transport. Numerous potential transcription factors binding sites at the site of integration were identified. Furthermore, the genes at integration site, transcription factors potentially binding upstream of HIV-1 promoter and factors that assist HIV-1 integration were found to be expressed at higher levels in cord than adult cells. These results may help explain a higher HIV-1 gene expression and replication in cord compared with adult cells. Finally, I have also made progress in the development of new and novel antivirals by showing that CD4-mimetic miniproteins significantly inhibited HIV-1 entry and replication in T-cell lines and primary blood mononuclear cells. In addition, several compounds from the crude extracts of endophytic fungi found in desert plants were able to inhibit HIV-1 replication in T-cell lines. Taken together, the results from this dissertation provide new insights into understanding the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression and replication in infants, as well as provide new possibilities for anti-retroviral drug development.

Name thesis:degree_name

PhD

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Immunobiology

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2007

Author dc:creator

• Wellensiek, Brian Philip

Advisor dc:contributor.advisor

• Ahmad, Nafees

Committee members dc:contributor.committeemember

• Bernstein, Harris
• Harris, David
• Schluter, Samuel

• Immunobiology

Statement dc: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.

Language dc:language.iso

EN

Handle dc:identifier.uri

http://hdl.handle.net/10150/195132

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/195132