Highly purified quiescent human peripheral blood CD4+ T cells are infectible by human immunodeficiency virus but do not release virus after activation

Abstract

Previous studies have suggested that resting CD4+ lymphocytes can be infected by human immunodeficiency virus (HIV), but viral production is inhibited. If these cells are activated, progeny virions are released. The present data indicate that CD4+ lymphocytes in the G0/G1 stage of the cell cycle which have been highly purified to remove macrophages and activated HLA-DR+ cells can also be infected by HIV. However, our findings differ from those of earlier reports since in this study, infected quiescent CD4+ cells cannot be activated to produce virus after virus inoculation. PCR analyses indicate that reverse transcription in these CD4+ cells is arrested at a very early step in proviral DNA formation (U3-R region). They do not show any evidence of longer DNA transcripts (e.g., U3-gag). When these quiescent infected CD4+ lymphocytes are activated by exposure to mitogens and macrophages and then reinoculated with HIV, the replication of virus takes place. Resting CD4+ lymphocytes are also resistant to infection when they are cocultured with HIV-infected macrophages. Only activated CD4+ cells are susceptible to cell-to-cell transmission. These observations suggest that in vivo tissue macrophages, susceptible to HIV replication, are the major cells initially productively infected by the virus. Then these cells can transfer HIV to activated CD4+ lymphocytes with resultant virus production. The presence of arrested reverse transcription in quiescent cells raises questions about the cellular factors required to permit production of longer HIV proviral DNA copies. Because they can be reinfected once they have been activated, these infected quiescent cells could be a source of recombinant viruses in the host.