Human immunodeficiency virus (HIV, HTLV-III, LAV, ARV) and ovine lentiviruses (OvLV) share morphological and genomic similarities and cause a persistent infection resulting in slow, progressive disease of lymphoid, respiratory, and nervous systems. Primary lymphoid interstitial pneumonia (LIP) in children and adults has recently been associated with HIV infection. LIP occurs as a common clinical manifestation of OvLV-induced disease in sheep and can be rapidly induced in neonatal lambs by injecting OvLV intratracheally. The purpose of the proposed research is to use this animal model of lentivirus infection to evaluate the relationship between lentivirus genomic structure and pathogenicity. To investigate the viral determinants of strain specific pathogenic and immunologic responses in lambs, two plaque purified OvLV isolates will be employed: 85/34, a highly lytic field isolate capable of inducing sever LIP within 12 weeks, and 84/28, an isolate that induces slowly progressive syncytia in vitro and is associated with ovine pulmonary carcinoma and LIP. The effects of host genetic variation will be minimized by use of isogeneic monozygotic twin lambs for inoculation. Seven pairs of lambs will be inoculated at birth with one of the isolates or with media. Pairs of animals will be chosen to evaluate reproducibility of lesions and immune responses both within a viral strain and between strains. Serum antibody levels, changes in bronchoalveolar cells, development of viremia, and cell-mediated cytotoxicity of virus-infected autologous and allogeneic target cells will be evaluated over a 5 month period. After sacrifice, lung, regional lymph nodes, spleen, and selected other organs will be assayed for presence of histologic lesions and infectious virus. Additionally, spontaneous interferon production by pulmonary lymphocytes will be quantitated for each lamb and correlated with lesions development. The viral strains will be molecularly cloned and compared at the nucleic acid level by restriction endonuclease mapping and hybridization. The viruses will be compared at the protein level in terms of molecular size and antigenic features of major structural proteins. Antigenic comparisons will be made using direct binding and competition radioimmunoassay, radioimmunoprecipitation of radiolabelled viral proteins, and immunoblotting of electrophoresed proteins. Correlations of nucleic acid structure and protein composition of each strain with pathogenicity and immune response differences will then be made.
