Expression of the CD4 glycoprotein, the surface receptor for the human immunodeficiency virus (HIV) (1-4), and of specific transcription factors that promote the expression of HIV genes (5) are characteristics that target a subset of lymphocytes for the pathological consequences of HIV infection. Additional properties of CD4+ lymphocytes and other HIV host cells could affect the efficiency of replication or the cytopathic effects of the virus, and thereby determine whether the outcome of infection is cell death; the establishment of a latent, nonproductive state; or the evolution of a chronic, virus-producing reservoir. The existence and potential importance of such host cell-specific factors is suggested by the variable response to HIV infection among cultured human lymphoid cell lines in vitro (6-8). The basis for this variability is poorly understood, and the spectrum of responses to HIV infection in vitro has not been well characterized.The regulation of deoxyribonucleotide pool size and turnover in host cells could affect the reverse transcription of the HIV genome and subsequent replication of double-stranded circular viral DNA, and could strongly influence the therapeutic activity or cytotoxicity of antiretroviral nucleoside analogs. In view of these possibilities, we initiated studies of the ability of HIV to infect mutant lymphoblastoid cell lines with altered nucleoside metabolism . We chose the CEM human T cell line (9) and the WIL-2 human B cell line (10) because they have been shown to differ strikingly in their regulation of deoxynucleotide metabolism (11,12), and because of the availability of mutants of each that are deficient in specific nucleoside kinase activities, which could be useful for studies of antiretroviral nucleoside analog metabolism. Here we report a systematic characterization ofthe responses ofthese mutants and other derivatives of CEM and WIL-2 to infection with the HTLV IIIB strain of HIV.