Role of β-chemokines in HIV-1 infection of dendritic cells maturing from CD34+ stem cells

Objectives: To study the susceptibility to infection by different strains of HIV-1 viruses and the roles of chemokines (macrophage inflammatory protein-1 alpha [MIP-1 alpha], MIP-1 beta, and regulated-on-activation-T-expressed-and-secreted [RANTES]) in CD34(+) stem cells maturing into dendritic cells (DC). Design: It has been controversial whether CD34(+) stem cells are susceptible to HIV-1 infection and whether high levels of beta-chemokines are beneficial for suppressing HIV-1 infection during DC maturation. These questions were addressed using different strains of HIV-1 and CD34(+) stem cells taken from cord blood and cultured with granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) to generate mature DC. Methods: CD34(+) stem cells were exposed with M-tropic virus Ba-L or T-tropic viruses IIIB or Rut at day 1. beta-Chemokines were added to some cells before the virus and kept throughout the culture. Virus replication was measured throughout the maturation of these cells into CD1a(+) DC and CD1a(-)CD14(+) cells using enzyme-linked immunosorbent assay (ELISA) for p24, nested polymerase chain reaction (PCR) for env and intracellular p24 detection by flow cytometry. Results: First, CD34(+) stem cells acquired or were infected by live virus because maturing cells showed infection by both M- and T-tropic viruses. Second, the viruses replicated actively during the maturation of CD34(+) stem cells toward CD1a(+) DC and CD1a(-) CD14(+) cells. Third, beta-chemokines suppressed infection by M-tropic virus Ba-L. And finally, beta-chemokines enhanced infection by T-tropic viruses IIIB and Rut. Conclusions: In addition to the initial anti-M-tropic virus effect by beta-chemokines, selective pressure on viruses may also result because of an increase in susceptibility to T-tropic virus. Caution should be taken when evaluating the effect of beta-chemokine receptor agonists in AIDS therapy.