Cellular Pathways for Productive HIV-1 Entry and Molecular Mechanisms of its Inhibition.
dc.contributor.author | Song, Hanna | en_US |
dc.date.accessioned | 2015-05-14T16:25:48Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2015-05-14T16:25:48Z | |
dc.date.issued | 2015 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/111418 | |
dc.description.abstract | Understanding of human immunodeficiency virus (HIV), productive viral entry, and its inhibition helps elucidate viral pathogenesis and further develop therapeutics aiming to block HIV entry. In this thesis, we focus on the cellular pathways that lead to productive infection and mechanisms of its inhibition by membrane-impermeable fusion inhibitors, using fluorescently-labeled HIV as an important tool. Although there have been many studies using fluorescently-labeled virions, understanding of their features in terms of infectivity, labeling efficiency, or intensity profiles has been limited. Our study characterizing fluorescently-labeled HIV-1 give us better understanding of HIV-1 and interpretation of data when using virions for mechanistic studies. Using the characterized HIV-1, we investigated entry pathways that lead to productive HIV-1 infection by seeking the potential correlation between the inhibition of cell endocytosis and the inhibition of HIV-1 infection. The results from different cell lines with various inhibitors blocking endocytosis suggest that endocytosis can indeed lead to productive infection, as revealed by the specific inhibition of HIV-1 infection by dynamin I K44A mutant. However, endocytosis may not be the only productive pathway for HIV-1 infection because all inhibition data that we have observed appear to be partial, which is in contrast to the inhibition by T20. For both antibodies and T20, HIV-1 infection can be blocked close to 100%, indicating that these drugs are efficacious enough although HIV can establish productive infection through endocytosis. These results also demonstrate that endocytosed virions need to fuse with endosomes for productive infection. The conclusion that endocytosis can initiate productive infection of HIV-1 led us to investigate whether the presence of endocytic entry may reduce T20 efficacy by allowing virus to escape from this membrane impermeable drug. To test this hypothesis, we examined the effect of T20 on HIV-1 internalization and the impact of endocytosis on T20 efficacy. These experiments show that endocytosis has no apparent effect on T20 efficacy, suggesting that endocytosis does not offer measurable advantage for the virus to escape from membrane-impermeable T20. Taken together, these studies suggest that endocytosis contributes to the productive entry of HIV-1, however, the efficacy of T20 is not affected by viral endocytosis. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Cellular Pathways for Productive HIV-1 Entry and Molecular Mechanisms of its Inhibition | en_US |
dc.title | Cellular Pathways for Productive HIV-1 Entry and Molecular Mechanisms of its Inhibition. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutical Sciences | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Cheng, Wei | en_US |
dc.contributor.committeemember | Collins, Kathleen L. | en_US |
dc.contributor.committeemember | Rosania, Gustavo | en_US |
dc.contributor.committeemember | Lee, Kyung-Dall | en_US |
dc.subject.hlbsecondlevel | Microbiology and Immunology | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/111418/1/skmkmin_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.