HIV-1 Infection of Hematopoietic Progenitor Cells.

HIV;Latent Infection;HIV Reservoirs;HIV Coreceptor Tropism;Microbiology and Immunology;Health Sciences;Microbiology & Immunology

McNamara, Lucy AlexandraOno, Akira ;

University of Michigan

关键词: HIV;    Latent Infection;    HIV Reservoirs;    HIV Coreceptor Tropism;    Microbiology and Immunology;    Health Sciences;    Microbiology & Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/96161/mcnamarl_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

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.