V3 Loop of Human Immunodeficiency Virus Type 1 Reduces Cyclin E Expression and Induces G 1 Arrest in Interleukin 2-Dependent T Cells

Abstract

We previously described that V3 loop derived from the HTLV-III BH10 clone V3-BH10 markedly suppressed IL-2-driven T cell proliferation and produced G₁ arrest of the cells. Here, we tested the effect of V3-BH10 on the molecules that are involved in transition from the G₁ to S phase of the cell cycle. The effect of V3-BH10 on the IL-2-induced expression of G₁ cyclins, Cdk inhibitors, and phosphorylation of retinoblastoma protein (pRb) was tested by immunoblotting, using the IL-2-dependent CD4-positive cell line Kit 225. Furthermore, IL-2-dependent kinase activity of the cyclin E–Cdk2 complex was investigated with histone H1 as a substrate. V3-BH10 reduced the IL-2-dependent expression of cyclin E, but not that of cyclin D and Cdk inhibitors such as p21 and p27. As the result of reduction of cyclin E, histone H1 kinase activity of the cyclin E–Cdk2 complex was markedly reduced even in the presence of rIL-2, followed by incomplete phosphorylation of pRb. The reduction in hyperphosphorylation of pRb by V3-BH10 led to G₁ arrest of the cell cycle. Thus, V3-BH10 induced G₁ arrest in IL-2-dependent cell cycle progression by reducing cyclin E expression, which may be one of the mechanisms underlying the dysfunction of T cells in HIV-1-infected people.