Abstract
ABSTRACTIn addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat−IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses.
Highlights
In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins
We reported that HIV-1 Tat physically interacted in vitro and in vivo with interferon regulatory factor 1 (IRF-1) [37,38,39], and we observed that coexpression of Tat and IRF-1 cause a reproducible decrease in IRF-1 accumulation
Analysis of the transcriptional activity of a 3,500-bp fragment of the IRF-1 promoter linked to the luciferase reporter gene indicated that the basal and tumor necrosis factor alpha (TNF-␣)-stimulated IRF-1 promoter activity was not affected by increasing amounts of Tat expression compared with cells expressing an empty vector (Fig. 1A)
Summary
In addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses. Among the numerous Tat-interacting proteins, we previously demonstrated that Tat interacted with interferon regulatory factor 1 (IRF-1), the founding member of a family of nine transcriptional regulators that impacts various physiological functions, including the immune response to viral infection, oncogenesis, and development of an immune system [13,14,15,16]. Later, when discrete amounts of Tat are produced and IRF-1 becomes dispensable for long terminal repeat (LTR) activity, interaction with Tat sequesters IRF-1, resulting in the quenching of its transcriptional activity on target genes [36,37,38,39]
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