Role of MIP-1beta and RANTES in HIV-1 infection of microglia: inhibition of infection and induction by IFNbeta.

Microglia are the major target of HIV-1 infection in the brain. Microglial infection is CD4-dependent, but the role of chemokine receptors CCR5 and CCR3 and their natural ligands in modulating HIV-1 infection in microglia has been questioned. In primary human fetal microglial cultures, we demonstrate that HIV-1 infection of these cells is dependent on CCR5, since an antibody to CCR5 completely blocked productive infection. Anti-CCR3, in contrast, had a smaller inhibitory effect which was not statistically significant. The chemokine ligands for CCR5, RANTES and MIP-1beta, also potently inhibited HIV-1 infection in microglia, but the third ligand MIP-1alpha failed to show inhibition. Interestingly, when microglial cultures were treated with antibodies specific to each of these chemokines, HIV-1 infection was enhanced by anti-RANTES and anti-MIP-1beta, but not by anti-MIP-1alpha. These results demonstrate the presence of endogenous chemokines that act as endogenous inhibitors of HIV-1 infection in microglia. Additionally, IFNbeta, a known anti-viral cytokine, also provided potent inhibition of viral infection as well as induction of all three chemokines in microglia. These results suggest the possibility that type I interferon can down-modulate microglial HIV-1 infection in vivo by multiple mechanisms.