Modeling bone marrow progenitor cell differentiation and susceptibility to HIV-1 infection

Aikaterini Alexaki

doi:10.17918/00000382

Bone marrow (BM) hematopoietic progenitor cells (HPCs) are susceptible to human immunodeficiency virus type 1 (HIV-1) to a limited extent, while differentiation induces their susceptibility. The growth and development of HPCs in the BM of HIV-1-infected patients is impaired due to the presence of HIV-1 proteins and changes in the cytokine milieu, leading to increased cell death of this population and potentially an altered maturation process. It has been hypothesized that events that occur in the BM may be involved in the generation of monocyte populations that are more susceptible to HIV-1, and potentially more neuroinvasive. To explore the possibility that factors impacting the differentiation process of HPC may also affect their susceptibility to HIV-1, a model of BM HPC differentiation was developed by using the TF-1 cell line, which represents HPCs arrested at an early stage of differentiation. It was shown that PMA induces TF-1 cell activation and differentiation through the myeloid lineage. Similarly, medium conditioned (CM) by PMA-treated cells induced differentiation of TF-1 cells and CCR5 and CXCR4 upregulation. Concurrent expression of the HIV-1 receptor and coreceptors on TF-1 cells ultimately contributed to increased susceptibility to HIV-1. PMA- and CM-induced differentiation of TF-1 cells also led to increased LTR activity, with Sp and NF-[kappa]B factors playing a crucial role in LTR-mediated transcription. A number of chemokines were found in the CM. IL-1[beta], which is present in the CM in small quantities appeared to induce differentiation, and CCR5 and CXCR4 upregulation on TF-1 cells, and may be partially responsible for the effects of CM. IL-1[beta], which has been shown to increase in the BM of HIV-1-infected patients, may have a physiologically important role in the differentiation of HPC in HIV-1-infected patients. Overall, these studies establish the TF-1 cell line as a model of HPC differentiation and indicate that differentiation of TF-1 cells may lead to increased susceptibility to HIV-1 infection. Additionally, to study LTR-driven transcription from an integrated chromatin-based microenvironment, a series of stably transfected cell lines were generated. Results indicated that specific nucleotide sequence configurations may be associated with latency in TF-1 cells.

Modeling bone marrow progenitor cell differentiation and susceptibility to HIV-1 infection

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Modeling bone marrow progenitor cell differentiation and susceptibility to HIV-1 infection

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