Functional Analysis of KAP1/TRIM28 Requirements for HIV-1 Transcription Activation

Keyera Randolph, Usman Hyder, Ashwini Challa, Erick Perez, Iván D’Orso

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

HIV-1 latency maintenance and reactivation are regulated by several viral and host factors. One such factor is Krüppel-associated box (KRAB)-associated protein 1 (KAP1: also named TRIM28 or TIF1β). While initial studies have revealed KAP1 to be a positive regulator of latency reversal in transformed and primary CD4+ T cells, subsequent studies have proposed KAP1 to be a repressor required for latency maintenance. Given this discrepancy, in this study, we re-examine KAP1 transcription regulatory functions using a chemical genetics strategy to acutely deplete KAP1 expression to avoid the accumulation of indirect effects. Notably, KAP1 acute loss partially decreased HIV-1 promoter activity in response to activating signals, a function that can be restored upon complementation with exogenous KAP1, thus revealing that KAP1-mediated activation is on target. By combining comprehensive KAP1 domain deletion and mutagenesis in a cell-based reporter assay, we genetically defined the RING finger domain and an Intrinsically Disordered Region as key activating features. Together, our study solidifies the notion that KAP1 activates HIV-1 transcription by exploiting its multi-domain protein arrangement via previously unknown domains and functions.

Original languageEnglish (US)
Article number116
JournalViruses
Volume16
Issue number1
DOIs
StatePublished - Jan 2024

Keywords

  • HIV-1 gene expression
  • KAP1
  • latency
  • TIF1β
  • transcription
  • TRIM28

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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