A small open reading frame (ORF) in maedi-visna virus (MVV) and caprine arthritis encephalitis virus (CAEV) was initially named "tat" by analogy with a similarly placed ORF in the primate lentiviruses. The encoded " Tat Lentiviruses comprise a genus of complex, nononcogenic retroviruses that infect diverse mammalian hosts, including primates (human immunodeficiency virus [HIV] and simian immunodeficiency virus), carnivores (feline immunodeficiency virus), and ungulates (equine infectious anemia virus, bovine immunodeficiency virus, and the small-ruminant lentiviruses [SRLV]). In addition to the three essential retroviral genes, gag, pol, and env, lentiviruses carry a variable number of regulatory and accessory genes, most of which are situated between the end of pol and the beginning of env. The most complex of these viruses, HIV type 1 (HIV-1), encodes three regulatory genes, tat, rev, and vif, and three accessory genes, vpu, vpr, and nef. The three conserved open reading frames found between pol and env in the SRLVs maedi-visna virus (MVV) and caprine arthritis-encephalitis virus (CAEV) have classically been assigned to the regulatory genes tat, rev, and vif.Some MVV-infected sheep progress to a stage of chronic debilitating disease affecting mainly the lungs (progressive interstitial pneumonia) and the central nervous system (progressive demyelinating encephalomyelitis) many years after infection (24,25). Goats infected by the related CAEV can develop leukoencephalomyelitis (young kids) or chronic arthritis and mastitis (adult animals) (5, 6). In vivo, MVV and CAEV chiefly replicate in cells of the monocyte/macrophage lineage, and

All lentiviruses contain an open reading frame located shortly upstream or inside of the env gene and encoding a small protein which has been designated Tat. This designation was mainly with respect to the positional analogy with the first exon of the trans-activator protein of the well studied human immunodeficiency virus type 1 (HIV-1). In this work we comparatively studied the trans- activation activity induced by Tat proteins of the small ruminant Maedi Visna virus (MVV) of sheep and Caprine arthritis encephalitis virus (CAEV) of goats on MVV and CAEV LTRs with that induced by the human lentivirus HIV-1 on its own LTR. The HIV-1 LTR alone weakly expresses the reporter GFP gene except when the HIV-1 Tat protein is coexpressed, the GFP expression is increased 60-fold. In similar conditions only minimal trans-activation increasing two- to three-fold the MVV and CAEV LTR activity was found with MVV Tat protein, and no trans-activation activity was detected in any used cell type or with any virus strain when CAEV Tat was tested. These results indicate that the small ruminant lentiviruses (SRLV) differ from the primate lentiviruses in their control of expression from the viral LTRs and put into question the biological role of the encoded protein named "Tat."

Lentiviruses have long been considered host-specific pathogens, but several recent observations demonstrated their capacity to conquer new hosts from different species, genera, and families. From these crossspecies infections emerged new animal and human infectious diseases. The successful colonization and adaptation of a lentivirus to a nonnatural host depends on unspecific and specific host barriers. Some of those barriers exert a relative control of viral replication (i.e., cytotoxic T-lymphocyte response, viral inhibitory factors), but none of them was found able to totally clear the infection once the retrovirus is fully adapted in its host. In this study we examined the evolution of the host-lentivirus interactions occurring in an experi-

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Caprine arthritis encephalitis virus (CAEV) is the natural lentivirus of goats, well known for its tropism for macrophages and its inability to cause infection in lymphocytes. The viral genome lacks nef, tat, vpu and vpx coding sequences. To test the hypothesis that when nef is expressed by the viral genome, the virus became toxic for lymphocytes during replication in macrophages, we inserted the SIVsmm PBj14 nef coding sequences into the genome of CAEV thereby generating CAEV-nef. This recombinant virus is not infectious for lymphocytes but is fully replication competent in goat macrophages in which it constitutively expresses the SIV Nef. We found that goat lymphocytes cocultured with CAEV-nef-infected macrophages became activated, showing increased expression of the interleukin-2 receptor (IL-2R). Activation correlated with increased proliferation of the cells. Interestingly, a dual effect in terms of apoptosis regulation was observed in exposed goat lymphocytes. Nef was found first to induce a protection of lymphocytes from apoptosis during the first few days following exposure to infected macrophages, but later it induced increased apoptosis in the activated lymphocytes. This new recombinant virus provides a model to study the functions of Nef in the context of infection of macrophages, but in absence of infection of T lymphocytes and brings new insights into the biological effects of Nef on lymphocytes.