Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. We examined whether HTLV could productively infect human hematopoietic progenitor cells. CD34 ؉ cells were enriched from human fetal liver cells and cocultivated with cell lines transformed with HTLV-1 and-2. HTLV-1 infection was established in between 10 and >95% of the enriched CD34 ؉ cell population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag expression was also detected in infected hematopoietic progenitor cells. HTLV-1-infected hematopoietic progenitor cells were cultured in semisolid medium permissive for the development of erythroid (BFU-E), myeloid (CFU-GM), and primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences were detected in colonies of all hematopoietic lineages; furthermore, the ratio of HTLV genomes to the number of human cells in each infected colony was 1:1, consistent with each colony arising from a single infected hematopoietic progenitor cell. Severe combined immunodeficient mice engrafted with human fetal thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1-infected T cells or enriched populations of CD34 ؉ cells established viral infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice with the greatest HTLV-1 proviral burdens showed increased expression of the CD25 marker and the interleukin 2 receptor alpha chain and perturbation of CD4 ؉ and CD8 ؉ thymocyte subset distribution profiles. Hematopoietic progenitor cells and thymuses may be targets for HTLV infection in humans, and these events may play a role in the pathogenesis associated with infection.

Differences in cellular function and viral protein expression between IgMhigh and IgMlow B-cells in bovine leukemia virus-infected cattle

“…These reports suggest that the increase in IgM high B-cells in the blood of BLV-infected cattle may be attributable to nonrecirculating immature B-cells derived from either bone marrow or Peyer's patches, which are the primary lymphoid organs responsible for B-cell development and B-cell diversity in cattle and sheep (Yasuda et al, 2006). In HTLV-1 infection, immature thymocytes are the targets for infection, and the emergence of malignant clones in the thymus may be selected over time in HTLV-1-infected patients (Feuer et al, 1996;Hasegawa et al, 2006). Thus, the progenitor cells of B-cells could be infected with BLV in the primary lymphoid organs.…”

Human T‐cell Leukemia Virus Type 1 Can Infect a Wide Variety of Cells in Mice

“…Human hematopoietic progenitor cells are susceptible to HTLV-1 infection in vitro, and HTLV-1 infection could be maintained during differentiation of the HTLV-1-infected hematopoietic progenitor cells into erythroid, myeloid and primitive progenitor colonies. 19) Previous reports had shown that the leukemia cells of one ATL patient expressed myeloid cell phenotypes, 20) and that HTLV-1 could infect human promyelocytic leukemia HL60 cells. 21) The spleen DNA from mice 2, 3, 7, 9, 10, 11, 12, 13 and 14, that harbored the HTLV-1 pX sequence in sorted cell lysates, was checked for the human-specific HERV-R sequence to see whether any MT-2 cells remained in the spleen.…”

The utilization of humanized mouse models for the study of human retroviral infections

“…Another interesting feature of the disease is the development of hypercalcemia in 70% of ATL patients. Hypercalcemia is thought to be the result of an increase in osteoclast activity and associated resorption of bone tissue that is mediated through factors such as macrophage colony-stimulating factor (M-CSF) and macrophage inflammatory protein-1α (MIP-1α) [ 82 , 84 , 136 , 145 ]. Additionally, parathyroid hormone-related protein (PTHrP) has also been implicated as an important factor in the development of HTLV-1 infection and subsequent transformation of T-lymphocytes [ 146 ].…”

“…Feuer et al . took a different approach when they used the previously mentioned SCID-hu Thy/Liv model to compare the engraftment achieved with either infected human hematopoietic progenitor CD34+ cells or in vitro transformed HTLV-1 infected cell lines SLB-1 and MT-2 [ 145 ]. This group showed that not only could human hematopoietic progenitor cells be infected via co-cultivation with cell lines transformed with HTLV-1 and HTLV-2, but upon inoculation into SCID-hu Thy/Liv mice, infection could be detected in biopsies from the thy/liv organ.…”