Human immunodeficiency virus type 1 (HIV-1) and human hematopoietic progenitor cells

ABSTRACT Although cells of monocytic lineage are the primary source of human immunodeficiency virus type 1 (HIV-1) in the brain, other cell types in the central nervous system, including astrocytes, can harbor a latent or persistent HIV-1 infection. In the present study, we examined whether immature, multipotential human brain-derived progenitor cells (nestin positive) are also permissive for infection. When exposed to IIIB and NL4-3 strains of HIV-1, progenitor cells and progenitor-derived astrocytes became infected, with peak p24 levels of 100 to 500 pg/ml at 3 to 6 days postinfection. After 10 days, virus production was undetectable but could be stimulated by the addition of tumor necrosis factor alpha (TNF-α). To bypass limitations to receptor entry, we compared the fate of infection in these cell populations by transfection with the infectious HIV-1 clone, pNL4-3. Again, transfected progenitors and astrocytes produced virus for 7 days but diminished to low levels beyond 8 days posttransfection. During the nonproductive phase, TNF-α stimulated virus production from progenitors as late as 5 weeks posttransfection. Astrocytes produced 5- to 20-fold more infectious virus (27 ng of p24/106 cells) than progenitors at the peak of 3 days posttransfection. Differentiation of infected progenitors toward an astrocyte phenotype increased virus production to levels consistent with infected astrocytes, suggesting a phenotypic difference in viral replication. Using this cell culture system of multipotential human brain-derived progenitor cells, we provide evidence that progenitor cells may be a reservoir for HIV-1 in the brains of AIDS patients.

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Expression of the Human Immunodeficiency Virus Type-1 Coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ Hematopoietic Progenitor Cells

Blood ◽

10.1182/blood.v89.10.3522 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3522-3528 ◽

Cited By ~ 99

Author(s):

Martin Deichmann ◽

Ralf Kronenwett ◽

Rainer Haas

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Progenitor Cells ◽

Hematopoietic Progenitor Cells ◽

Cd4 Cells ◽

Hematopoietic Progenitor ◽

Cd34 Cells ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract CD34+ hematopoietic progenitor cells were assessed for mRNA expression of the human immunodeficiency virus type-1 (HIV-1) coreceptors CXCR-4, also termed fusin or LESTR, and CKR-5, also called CC-CKR-5 or CCR-5. The CD34+ cells were obtained from leukapheresis products of 17 patients after granulocyte colony-stimulating factor–supported cytotoxic chemotherapy. Using a two-step enrichment procedure including immunomagnetic bead separation and fluorescence-activated cell sorting, the CD34+ cells had a median purity of 99.8%. Assessing 9 CD34+ cell samples by polymerase chain reaction after reverse transcription (RT-PCR), CXCR-4 mRNA was found in all samples, whereas CKR-5 mRNA was only present in 3 samples, even though a nested PCR was used. Eight additional CD34+ cell samples were sorted according to CD4 expression. Based on a three-color immunofluorescence analysis, the mean relative fluorescence intensity of HLA-DR was smaller on CD34+/CD4+ cells in comparison with CD34+/CD4− cells. CXCR-4 mRNA was found in 5 of 8 CD34+/CD4+ samples and in 7 of 8 CD34+/CD4− samples, whereas CKR-5 mRNA was detected in 2 CD34+/CD4+ samples and in 1 CD34+/CD4− cell sample. Looking at the total number of CD34+ cell samples examined, the proportion of specimens containing CXCR-4 mRNA was 84% in comparison with 24% of specimens positive for CKR-5 mRNA. These data suggest that CD34+/CD4+ hematopoietic progenitor cells, including true stem cell candidates, could be susceptible to HIV-1 infection. Considering the relatively low incidence of CD34+ cell samples containing CKR-5 mRNA, CD34+/CD4+ cells appear to be particularly prone for HIV-1 infection via the CXCR-4 coreceptor. Because this chemokine receptor allows T-cell–tropic HIV-1 strains to infect cells, CD34+ cells expressing CD4 and CXCR-4 might be infected by HIV-1 during later stages of the disease, following a viral phenotype switch from macrophage- to T-cell–tropic HIV-1 strains.

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Expression of the Human Immunodeficiency Virus Type-1 Coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ Hematopoietic Progenitor Cells

Blood ◽

10.1182/blood.v89.10.3522.3522_3522_3528 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3522-3528 ◽

Cited By ~ 1

Author(s):

Martin Deichmann ◽

Ralf Kronenwett ◽

Rainer Haas

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Progenitor Cells ◽

Hematopoietic Progenitor Cells ◽

Cd4 Cells ◽

Hematopoietic Progenitor ◽

Cd34 Cells ◽

Immunodeficiency Virus ◽

Hiv 1

CD34+ hematopoietic progenitor cells were assessed for mRNA expression of the human immunodeficiency virus type-1 (HIV-1) coreceptors CXCR-4, also termed fusin or LESTR, and CKR-5, also called CC-CKR-5 or CCR-5. The CD34+ cells were obtained from leukapheresis products of 17 patients after granulocyte colony-stimulating factor–supported cytotoxic chemotherapy. Using a two-step enrichment procedure including immunomagnetic bead separation and fluorescence-activated cell sorting, the CD34+ cells had a median purity of 99.8%. Assessing 9 CD34+ cell samples by polymerase chain reaction after reverse transcription (RT-PCR), CXCR-4 mRNA was found in all samples, whereas CKR-5 mRNA was only present in 3 samples, even though a nested PCR was used. Eight additional CD34+ cell samples were sorted according to CD4 expression. Based on a three-color immunofluorescence analysis, the mean relative fluorescence intensity of HLA-DR was smaller on CD34+/CD4+ cells in comparison with CD34+/CD4− cells. CXCR-4 mRNA was found in 5 of 8 CD34+/CD4+ samples and in 7 of 8 CD34+/CD4− samples, whereas CKR-5 mRNA was detected in 2 CD34+/CD4+ samples and in 1 CD34+/CD4− cell sample. Looking at the total number of CD34+ cell samples examined, the proportion of specimens containing CXCR-4 mRNA was 84% in comparison with 24% of specimens positive for CKR-5 mRNA. These data suggest that CD34+/CD4+ hematopoietic progenitor cells, including true stem cell candidates, could be susceptible to HIV-1 infection. Considering the relatively low incidence of CD34+ cell samples containing CKR-5 mRNA, CD34+/CD4+ cells appear to be particularly prone for HIV-1 infection via the CXCR-4 coreceptor. Because this chemokine receptor allows T-cell–tropic HIV-1 strains to infect cells, CD34+ cells expressing CD4 and CXCR-4 might be infected by HIV-1 during later stages of the disease, following a viral phenotype switch from macrophage- to T-cell–tropic HIV-1 strains.

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Targeting c-Mpl for Revival of Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition When CD34+ Progenitor Cells Are Re-Engrafted into a Fresh Stromal Microenvironment In Vivo

Journal of Virology ◽

10.1128/jvi.78.20.11385-11392.2004 ◽

2004 ◽

Vol 78 (20) ◽

pp. 11385-11392 ◽

Cited By ~ 10

Author(s):

Prasad S. Koka ◽

Christina M. R. Kitchen ◽

Srinivasa T. Reddy

Keyword(s):

Human Immunodeficiency Virus ◽

Progenitor Cells ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Severe Combined Immunodeficiency ◽

Stromal Microenvironment ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34+ progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34+ cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl+ CD34+ cells relative to c-Mpl− CD34+ cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl− CD34+ cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34+ progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34+ cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34+ cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl− CD34+ subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34+ cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals.

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