MODULATION OF FELINE IMMUNODEFICIENCY VIRUS-INFECTION BY STROMAL CELL-DERIVED FACTOR

The alpha-chemokine receptor CXCR4 has recently been shown to support syncytium formation mediated by strains of feline immunodeficiency vir us (FIV) that have been selected for growth in the Crandell feline kid ney cell line (CrFK-tropic virus). Given that both human and feline CX CR4 support syncytium formation mediated by FN, we investigated whethe r human stromal cell-derived factor (SDF-1) would inhibit infection wi th FIV. Human SDF-1 alpha and SDF-1 beta bound with a high affinity (K (D)s of 12.0 and 10.4 nM, respectively) to human cells stably expressi ng feline CXCR4, and treatment of CrFK cells with human SDF-1 alpha re sulted in a dose-dependent inhibition of infection by FIVPET. No inhib itory activity was detected when the interleukin-2 (IL-2)-dependent fe line T-cell line Mya-1 was used in place of CrFK cells, suggesting the existence of a CXCR4-independent mechanism of infection, Furthermore, neither the human beta-chemokines RANTES, MIP-1 alpha, MIP-1 beta, an d MCP-1 nor the alpha-chemokine IL-8 had an effect on infection of eit her CrFK or Mya-l cells with CrFK-tropic virus. Envelope glycoprotein purified from CrFK-tropic virus competed specifically for binding of S DF-1 alpha to feline CXCR4 and CXCR4 expression was reduced in FN-infe cted cells, suggesting that the inhibitory activity of SDF-1 alpha in CrFK cells may be the result of steric hindrance of the virus-receptor interaction following the interaction between SDF and CXCR4. Prolonge d incubation of CrFK tells with SDF-1 alpha led to an enhancement rath er than an inhibition of infection. Flow cytometric analysis revealed that this effect may be due Largely to up-regulation of CXCR4 expressi on by SDF-1 alpha on CrFK cells, an effect mimicked by treatment of th e cells with phorbol myristate acetate, The data suggest that infectio n of feline cells with FIV can be mediated by CXCR4 and that, dependin g on the assay conditions, infection can be either inhibited or enhanc ed by SDF-1 alpha. Infection with FIV may therefore prove a valuable m odel in which to study the development of novel therapeutic interventi ons for the treatment of AIDS.