Hovden A-O, Sommerfelt MA. The influence of CD4 and CXCR4 on maedi-visna virus-induced syncytium formation. APMIS 2002;110:697–708. CD4 is the principal binding site for human and simian immunodeficiency virus (HIV/SIV) receptor interactions and the α chemokine receptor CXCR4 has been implicated as a primordial lentivirus receptor. This study sought to determine the relevance of CD4 and CXCR4 in virus-receptor interactions for the prototype lentivirus, maedi-visna virus (MVV) of sheep. Neither CD4 nor α/β chemokine receptors represent principal receptors for MVV since human osteosarcoma cells devoid of these molecules were susceptible to productive infection. Interestingly, the presence of either CD4 and/or CXCR4 on indicator cells dramatically enhanced MVV-induced cell fusion (syncytium formation) for three independent virus strains. Syncytium formation results from virus-receptor interactions and can be inhibited by receptor ligands. However, neither SDF-1α that binds CXCR4 nor recombinant gp120 (rgp120) that binds CD4 could specifically inhibit the observed enhancement of MVV-induced cell fusion under conditions that significantly reduced HIV-1-induced cell fusion. Our observations suggest that CD4 and CXCR4 may represent optional auxiliary components of an MVV receptor (or receptor complex) that facilitate MVV-mediated membrane fusion events, a feature important for virus entry. This potential accessory role for CXCR4 in MVV receptor interactions may reflect the distant relationship between the ovine (MVV) and the human/feline lentiviruses (HIV/FIV).