Separation of human immunodeficiency virus type 1 replication from nef-mediated pathogenesis in the human thymus

Human immunodeficiency virus type 1 (HIV-1) is frequently attenuated after long-term culture in vitro. The attenuation process probably involves mutat ions of functions required for replication and pathogenicity in vivo. Analy sis of attenuated HIV-1 for replication and pathogenicity in vivo will help to define these functions. In this study, we examined the pathogenicity of an attenuated HIV-1 isolate in a laboratory worker accidentally exposed to a laboratory-adapted HIV-1 isolate. Using heterochimeric SCID-hu Thy/Liv m ice as an in vivo model, we previously defined HIV-1 env determinants (HXB/ LW) that reverted to replicate in vivo (L. Su, H. Kaneshima, M. L. Bonyhadi , R. Lee, J. Auten, A. Wolf, B. Du, L. Rabin, B. H, Rahn, E. Terwilliger, a nd J. M. McCune, Virology 227:46-52, 1997). Here we further demonstrate tha t HIV-1 replication in vivo can be separated from its pathogenic activity, in that the HXB/LW virus replicated to high levels in SCID-hu Thy/Liv mice, with no significant thymocyte depletion. Restoration of the nef gene in th e recombinant HXB/LW genome restored its pathogenic activity, with no signi ficant effect on HIV-1 replication in the thymus. Our results suggest that in vitro-attenuated HIV-1 lacks determinants for pathogenicity as well as f or replication in vivo. Our data indicate that (i) the replication defect c an be recovered in vivo by mutations in the env gene, without an associated pathogenic phenotype, and (ii) nef can function in the HXB/LW clone as a p athogenic factor that does not enhance HIV-1 replication in the thymus, Fur thermore, the HXB/LW virus may be used to study mechanisms of HIV-1 nef-med iated pathogenesis in vivo.