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111 CCR5 Expression and ?-Chemokine Production during Cord Monocyte Differentiation: Implications for HIV-1 Infection of Neonatal Monocytes/Macrophages
X. Wang*, D. Zylla, E. Bergenstal, S. D. Douglas, Y. Li, J. Merrill, S. E. Starr, and W. Z. Ho
The Children's Hosp. of Philadelphia, Univ. of Pennsylvania Sch. of Med., USA
Background: Monocytes/macrophages are important targets for HIV. The stage of maturation of monocytes affects their susceptibility to HIV infection. The beta-chemokine receptor CCR5 is a major coreceptor for HIV entry into macrophages. Thus, we examined the correlation between expression of CCR5 and beta-chemokine production with susceptibility to HIV infection during cord monocytes differentiation.
Methods: Monocytes were isolated from 10 placental cord blood samples and cultured in 48-well plates (0.5 ( 106 cells/well). The cells were examined for CCR5 expression and ?-chemokine production every 2 days up to 10 days in cultures. Susceptibility of the cells cultured in vitro at different time points to HIV infection was also determined.
Results: Although the levels of CCR5 mRNA expression in freshly isolated cord monocytes are comparable to that in macrophages, cord monocytes expressed significantly lower levels of CCR5 protein on the cell surface than cord macrophages. Steady increases of CCR5 protein expression on cell membranes were observed during cord monocyte differentiation in vitro and were correlated with increased susceptibility to HIV infection by cord macrophages. A monoclonal antibody to CCR5 (2D7) blocked HIV Bal infection of cord macrophages, indicating that there is a direct association between CCR5 expression and the susceptibility to HIV infection. In addition, although there was no significant difference in endogenous beta-chemokine production between cord monocytes and macrophages, HIV infection of cord macrophages significantly enhanced macrophage inflammatory protein MIP-1alpha and MIP-1beta. The increased expression of these beta-chemokines was correlated with HIV replication in cord macrophages.
Conclusions: Taken together, Our data demonstrated that placental cord monocyte differentiation in vitro is associated with increased expression of CCR5 receptor, which contributes to the susceptibility of these cells to HIV infection. Our data provide further evidence that CCR5 plays a critical role in HIV-1 infection of cord monocytes/macrophages.
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