CXCR4 and CCR5 expression delineates targets for HIV-1 disruption of T cell differentiation.
HIV-1 disease is often associated with CD4+ T lymphopenia as well as quantitative reductions in naive CD8+ T cells and cytopenias involving nonlymphoid hemopoietic lineages. Studies in HIV-1-infected humans as well as in animal models of lenti-virus disease indicate that these effects may be secondary to infection and destruction of multilineage and lineage-restricted hemopoietic progenitor cells. To define the stages of T cell differentiation that might be susceptible to HIV-1, we performed flow cytometric analysis of the surface expression of CXCR4 and CCR5 on T cells and their progenitors from fetal tissue, cord blood, SCID-hu Thy/Liv mice, and adult peripheral blood. We found that CXCR4 is expressed at low levels on hemopoietic progenitors in the bone marrow, is highly expressed on immature (CD3-CD4+CD8-) T cell progenitors in the thymus, and then is down-regulated during thymocyte differentiation. As thymocytes leave the thymus and enter the peripheral circulation, the expression of CXCR4 is again up-regulated. In contrast, CCR5 is undetectable on most hemopoietic progenitors in the bone marrow and on intrathymic T progenitor cells. It is up-regulated when thymocytes coexpress CD4 and CD8, then down-regulated either in the thymus (CD4+ cells) or during exit from the thymus (CD8+ cells). These results indicate that discrete, lineage-related populations of T cell progenitors may vary widely in their potential to respond to chemokines and to be infected by HIV-1, and that T lymphoid differentiation is particularly vulnerable to CXCR4-using viruses.
Berkowitz
R D
RD
Gladstone Institute of Virology and Immunology, San Francisco, CA 94141-9100, USA.
Beckerman
K P
KP
Schall
T J
TJ
McCune
J M
JM
D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D016513:Mice, SCID; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000097:blood; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000097:blood; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism* / Q000821:virology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
D019713:Receptors, CCR5; D019718:Receptors, CXCR4