AbstractIt was proposed recently that CEM CD4‐positive T cells infected chronically by herpes simplex virus type 1 (HSV‐1) and human immunodeficiency virus type 1 (HIV‐1) (CEMHSV/HIV) may be used as a model for studying HIV/HSV interactions. To ascertain whether HSV‐HIV coinfection of T lymphocytes has a role in promoting progression of lentiviral infection, T cells infected chronically by either HSV‐1 (CEMHSV) or HIV‐1 (CEMHIV) were challenged with a superinfecting dose of HIV‐1 or HSV‐1. The results show a positive influence on HIV growth when CEMHIV cells were superinfected with HSV‐1 to an extent that was dependent on the multiplicity of superinfection used. In contrast, HIV superinfection of CEMHSV cells resulted in a delay of HIV‐1 production and in a lack of HSV‐mediated LTR transactivation. These effects were due to cell growth inhibition and apoptosis, resulting from persistent HSV‐1 infection. Treatment of CEMHSV with acyclovir inhibited completely the HSV‐1 cytopathic effects and allowed efficient HIV‐1 replication. These data may be relevant in clarifying the role of HIV/HSV interaction in the pathogenesis of AIDS. J. Med. Virol. 70:163–170, 2003. © 2003 Wiley‐Liss, Inc.