Myxoma virus induces extensive CD4 downregulation and dissociation of p56^lck in infected rabbit CD4⁺ T lymphocytes

Myxoma virus is a pathogenic poxvirus that induces extensive dysregulation of cellular immunity in infected European rabbits. Infection of a rabbit CD4⁺ T-cell line (RL-5) with myxoma virus results in dramatic reductions of cell surface levels of CD4 as monitored by flow cytometry. The virus-induced downregulation of CD4 requires early but not late viral gene expression and could not be inhibited by staurosporine, an inhibitor of protein kinase C, which effectively blocks phorbol 12-myristate-13-acetate-induced downregulation of CD4. The decrease in total cellular levels of CD4 during myxoma virus infection could be inhibited by the lysosomotrophic agent NH₄Cl, suggesting a lysosomal fate for CD4 during myxoma virus infection. Steady-state levels of the CD4-associated protein tyrosine kinase p56^lck remained unchanged during myxoma virus infection, suggesting that p56^lck dissociates from CD4 prior to CD4 degradation in virus infected cells. Total p56^lck kinase activity was unaffected during myxoma virus infection, although the amount of p56^lck physically associated with CD4 declined in parallel with the loss of CD4. Thus, myxoma virus infection of CD4⁺ T lymphocytes triggers CD4 downregulation via a protein kinase C-independent pathway, causing the dissociation of p56^lck and the degradation of CD4 in lysosomal vesicles.