Tracking influenza A virus entry and infection: Implications of the immune response

Influenza A is capable of infecting human mononuclear leukocytes (MNL) and although the infection is abortive, without production of progeny virus, viral proteins are synthesized by infected cells. We have shown that influenza virus binds to CD3+, CD4+, CD8+ and CD19+ (B) lymphocytes but infection of the cells occurred only if cocultured with monocytes-macrophages. The mechanism of monocyte-macrophage facilitation of lymphocyte infection remains unknown. The percent of monocyte-macrophages and lymphocytes positive for expression of intercellular adhesion molecule-1 (ICAM-1) and leukocyte functional antigen-1 (LFA-1) increased after influenza virus exposure. Treatment of cells with antibodies specific for ICAM-1 or ICAM-1 plus LFA-1 reduced the infection of lymphocytes. Cell-cell contact was shown to be necessary but supernatant fluids from infected monocyte-macrophages were not sufficient to support infection of lymphocytes.; Activation of lymphocytes has been studied in general detail but the role that cell activation plays in influenza infection or in induction of apoptosis was unclear. CD3 +CD69+ as well as CD3+CD69− cells can be shown to produce viral proteins and both of these CD3+ subpopulations contain TUNEL positive (apoptotic) cells. Binding of virus to the surface of lymphocytes did not activate cells or induce apoptosis. Inactivated influenza virus activated lymphocytes exposed in the presence of monocytes-macrophages and induced low levels of apoptosis. Although similar percentages of CD4+ and CD8+ lymphocytes bind and internalize virus, significantly more CD8+ were lost through induction of apoptosis. Influenza virus exposure induced the expression of Fas on lymphocytes as well as FasL on T cells and monocytes-macrophages. Fas-FasL was shown to play a role in induction of apoptosis after influenza virus exposure but monocyte-macrophage depletion was more effective in reducing the level of apoptosis than the use of agonistic or blocking anti-FasL antibodies. Thus, restriction of lymphocyte infection as well as induction of apoptosis, while monocyte-macrophage-dependent, did not rely solely on cell activation or production of viral proteins. The development of an immune response to influenza virus thus occurs concomitant with and may depend upon monocyte-macrophage-dependent lymphocyte infection, activation, and apoptosis.