HIV-1 Infection of Hematopoietic Progenitor Cells.

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.PhDMicrobiology & ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/96161/1/mcnamarl_1.pd