E Böhnlein

HIV-1, HTLV-1 and normal T-cell growth: transcriptional strategies and surprises

In this review, Warner Greene and colleagues discuss recent studies that have revealed an intriguing molecular interplay between two pathogenic human retroviruses, HIV-1 and HTLV-1, and certain cellular genes that normally control T-cell growth. Activation of T cells during an immune response results in the induction of select transcription factors that bind specifically to kappa B enhancer elements present in both the IL-2R alpha and IL-2 genes. Normal T-cell growth is in part regulated by the transient expression of these genes. The Tax protein of HTLV-1 induces these same kappa B-specific proteins, but in contrast to immune stimulation, HTLV-1 infection of T cells leads to constitutive IL-2R alpha gene expression and immortalization. A second human retrovirus, HIV-1, can subvert the normal action of the kappa B-binding factors induced by these immune stimuli. Rather than promoting T-cell growth, these factors may augment viral replication and promote T-cell death.

HIV-1, HTLV-I and the interleukin-2 receptor: insights into transcriptional control.

In this study, we present direct evidence for the binding of the inducible cellular protein, HIVEN86A, to a 12-bp element present in the IL-2R alpha promoter. This element shares significant sequence similarity with the NF-kappa B binding sites present in the HIV-1 and kappa immunoglobulin enhancers. Transient transfection studies indicate that this kappa B element is both necessary and sufficient to confer tax or mitogen inducibility to a heterologous promoter. As summarized schematically in Fig. 5, the findings suggest that the HIVEN86A protein may play a central role in the activation of cellular genes required for T-cell growth, specifically the IL-2R alpha gene. In addition, the induced HIVEN86A protein also binds to a similar sequence present in the HIV-1 LTR leading to enhanced viral gene expression and ultimately T-cell death. Thus, mitogen activation of the HIV-1 LTR appears to involve the same inducible transcription factor(s) that normally regulates IL-2R alpha gene expression and T-cell growth. These findings further underscore the importance of the state of T-cell activation in the regulation of HIV-1 replication. Our results also demonstrate that HIVEN86A is induced by the tax protein of HTLV-I. Thus, in HTLV-I infected cells, normally the tight control of the transient expression of the IL-2R alpha gene is lost. The constitutive high-level display of IL-2 receptors may play a role in leukemic transformation mediated by HTLV-I (ATL). Apparently by the same mechanism, the tax protein also activates the HIV-1 LTR through the induction of HIVEN86A.(ABSTRACT TRUNCATED AT 250 WORDS)