The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34+ hematopoietic progenitor cells is primarily determined by their maturation stage

Dendritic cells (DC) were sorted on day 8 from cultures of CD34(+) cells with stem cell factor/Flt-3 ligand/granulocyte-macrophage colony-stimulating factor (GM-CSF)/tumor necrosis factor-alpha (TNF-alpha)/interleukin-4 (IL-4). Exposing immature CCR5(+)CXCR4(lo/-) DC to CCR5-dependent human immunodeficiency virus (HIV)-1(Ba-L) led to productive and cytopathic infection, whereas only low virus production occurred in CXCR4-dependent HIV-1(LAI)-exposed DC. PCR analysis of the DC 48 hours postinfection showed efficient entry of HIV-1(Ba-L) but not of HIV-1(LAI). CD40 ligand- or monocyte-conditioned medium-induced maturation of HIV-1(Ba-L)-infected DC reduced virus production by about 1 Log, while cells became CCR5(-). However, HIV-1(Ba-L)-exposed mature DC harbored 15-fold more viral DNA than their immature counterparts, ruling out inhibition of virus entry. Simultaneously, CXCR4 upregulation by mature DC coincided with highly efficient entry of HIV-1(LAI) which, nonetheless, replicated at the same low level in mature as in immature DC. In line with these findings, coculture of HIV-1(Ba-L)-infected immature DC with CD3 monoclonal antibody-activated autologous CD4(+) T lymphocytes in the presence of AZT decreased virus production by the DC. Finally, whether they originated from CD1a(+)CD14(-) or CD1a(-)CD14(+) precursors, DC did not differ as regards permissivity to HIV, although CD1a(+)CD14(-) precursor-derived immature DC could produce higher HIV-1(Ba-L) amounts than their CD1a(-)CD14(+) counterparts. Thus, both DC permissivity to, and capacity to support replication of, HIV is primarily determined by their maturation stage. (C) 1999 by The American Society of Hematology.