Differences in affinity of binding of lymphocytic choriomeningitis virus strains to the cellular receptor alpha-dystroglycan correlate with viral tropism and disease kinetics

alpha -Dystroglycan (alpha -DG) was recently identified as a receptor for l ymphocytic choriomeningitis virus (LCMV) and several other arenaviruses, in cluding Lassa fever virus (W. Cao, M. D. Henry, P. Borrow, H. Yamada, J. H. Elder, E. V. Ravkov, S. T. Nichol, R. W. Compans, K. P. Campbell, and M. B . A. Oldstone, Science 282:2079-2081, 1998). Data presented in this paper i ndicate that the affinity of binding of LCMV to or DG determines viral trop ism and the outcome of infection in mice. To characterize this relationship , we evaluated the interaction between alpha -DG and several LCMV strains, variants, and reassortants. These viruses could be divided into two groups with respect to affinity of binding to alpha -DG, dependence on this protei n for cell entry, viral tropism, and disease course. Viruses that exhibited high-affinity binding to alpha -DG displayed a marked dependence on alpha -DG for cell entry and were blocked from infecting mouse 3T6 fibroblasts by 1 to 4 nM soluble alpha -DG. In addition, high-affinity binding to alpha - DG correlated with an ability to infiltrate the white pulp (T-dependent) ar ea of the spleen, cause ablation of the cytotoxic T-lymphocyte (CTL) respon se by day 7 postinfection, and establish a persistent infection. In contras t, viruses,vith a lower affinity of binding to alpha -DG were only partiall y inhibited from infecting alpha -DG(-/-) embryonic stem cells and required a concentration of soluble alpha -DG higher than 100 nM to prevent infecti on of mouse 3T6 fibroblasts. These viruses that bound at low affinity were mainly restricted to the splenic red pulp, and the host generated an effect ive CTL response that rapidly cleared the infection. Reassortants of viruse s that bound to alpha -DG at high and low affinities were used to map genes responsible for the differences described to the S RNA, containing the vir us attachment protein glycoprotein 1.