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.