HIV-1 Infection of Hematopoietic Progenitor Cells.
dc.contributor.author | McNamara, Lucy Alexandra | en_US |
dc.date.accessioned | 2013-02-04T18:09:56Z | |
dc.date.available | 2013-02-04T18:09:56Z | |
dc.date.issued | 2012 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/96161 | |
dc.description.abstract | Latent HIV infection allows virus to persist in HIV-infected individuals in spite of antiretroviral therapy. In addition to the well-studied reservoir of latent virus in resting memory CD4+ T cells, we have recently proposed that hematopoietic progenitor cells (HPCs) in the bone marrow serve as a reservoir for latent HIV. Here, I first investigate whether HIV envelope tropism impacts the ability of the virus to infect different types of HPCs. I find that HIV envelopes that are able to use CXCR4 as a co-receptor permit infection of immature, multipotent HPCs defined by expression of the cell surface marker CD133, whereas CCR5-tropic HIV has a greatly reduced capacity to infect these cells. Furthermore, I find that a CXCR4-tropic HIV envelope can infect hematopoietic stem cells that support long-term, multilineage engraftment in mice. As hematopoietic stem cells can live for the entire lifespan of a person, latent HIV infection of these cells could create a very long-lived reservoir of virus. I next examine the cellular factors that promote latency in HPCs and find that HIV can establish a latent infection in multiple HPC subsets, including immature HPCs. Latent infection in these cells can be reversed by activation of the transcription factor NF-kappaB as well as by inhibition of histone deacetylases. Finally, I investigate whether the CD133+ subset of HPCs harbors HIV genomes in HAART-treated patients with undetectable viral loads. I detect HIV genomes in CD133-sorted cell populations in 6 of 11 donors, including two donors who have had undetectable viral loads for more than 8 years. Furthermore, for at least 5 of these 6 donors I demonstrate that CD3+ T cells are present at extremely low levels in the CD133-sorted populations and are therefore unlikely to contribute to the HIV DNA detected in these samples. Together, these findings illuminate the potential of long-lived, CD133+ HPCs to serve as a reservoir for latent virus in HIV-infected individuals. Further study of how latent infection in HPCs and T cells can be reversed to eliminate these viral reservoirs may lead us closer to a cure for HIV. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | HIV | en_US |
dc.subject | Latent Infection | en_US |
dc.subject | HIV Reservoirs | en_US |
dc.subject | HIV Coreceptor Tropism | en_US |
dc.title | HIV-1 Infection of Hematopoietic Progenitor Cells. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Microbiology & Immunology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Collins, Kathleen L. | en_US |
dc.contributor.committeemember | Moran, John V. | en_US |
dc.contributor.committeemember | Telesnitsky, Alice | en_US |
dc.contributor.committeemember | Ono, Akira | en_US |
dc.subject.hlbsecondlevel | Microbiology and Immunology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/96161/1/mcnamarl_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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