Activation/proliferation and apoptosis of bystander goat lymphocytes induced by a macrophage-tropic chimeric caprine arthritis encephalitis virus expressing SIV Nef

Abstract

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.

Genetic Characterization of HIV Type 1 Nef-Induced Vesicle Secretion

“…[49][50][51] (4) A chimeric caprine arthritis-encephalitis virus (CAEV) construct expressing Nef from SIVsmm PBj14 nef was used to infect goat macrophages. 52 This led to activation and apoptosis in cocultured goat lymphocytes, even though these lymphocytes were not sensitive to infection with the virus. In a recent study, Homann et al 53 examined HIV productive infection of human lymphoid aggregate ex vivo cultures (HLAC) from tonsil with viruses containing various Nef mutants to analyze which of Nef's activities contribute to HIV pathogenesis.…”

Changes of biological properties and pathogenesis of CAEV chimeras expressing Nef and Vpx/Vpr accessory proteins in infected goats

“…We generated CAEV chimeras by inserting nef or vpx/vpr or both coding sequences in the genome of CAEV [ 1 , 2 ]. All chimeras replicated productively and expressed their transgenes in infected target cells.…”

Apoptotic events induced by prototype foamy virus infection

“…Upon binding of a ligand to the death receptor, the consecutive activation of caspase-8 and caspase-3 ultimately leads to apoptosis. We investigated whether PFV infection also induced by death receptor or extrinsic pathway (Bouzar et al 2007). As shown in Figure 4(c), trivial amount or no significant fold change was observed in PFV-infected BHK-21 cells, comparing to mock cells.…”