Dependence on host cell cycle for activation of human immunodeficiency virus type 1 gene expression from latency

Human immunodeficiency virus type 1 (HIV-1) establishes latent infection of a certain population of CD4+ host cells which could be long-term reservoirs for HIV-1. The expression of viral genes in such long-term infected cells is strongly regulated by cellular status, such as the phase of the cell cycle or stage of cell differentiation. Here, viral gene expression in synchronized U1 cells, a monocytic cell clone latently infected with HIV-1, was characterized. The expression of HIV-1 antigens was detected exclusively at G2/M phase in U1 cells, irrespective of phorbol myristate acetate (PMA) treatment. The induction of HIV-1 gene expression in PMA-treated cells was due to the recruitment of NF-kappaB with DNA-binding activity at G2/M phase. Activated NF-kappaB was induced only by PMA treatment during the late G1 to S, but not after entering G2 phase, indicating that the transcriptional factor(s) involved in viral gene expression is also largely regulated by the host cell cycle. In contrast, the enhancement of antigen expression by treatment with tumour necrosis factor-alpha (TNF-alpha) was cell cycle-independent. In fact, NF-kappaB was activated 2 h after TNF-alpha treatment at all stages of the cell cycle. Thus, the mechanisms of HIV-1 activation from latency in U1 cells by PMA and TNF-alpha treatment are different. The model system using U1 cells shown here may provide insight into the mechanisms responsible for HIV-1 gene expression from latency.