HIV-1 Vpr induces an NFAT-controlled transcriptional program in primary CD4+ T cells

Area of Science:

• Virology and Immunology
• Molecular Biology
• Transcriptomics

Background:

• HIV-1 Vpr protein profoundly affects the host cell proteome and transcriptome.
• Vpr activates the nuclear factor of activated T cells (NFAT), a crucial transcription factor in T cells.
• The extent to which Vpr-induced transcriptional changes are mediated by NFAT in primary CD4+ T cells was previously unclear.

Purpose of the Study:

• To determine the proportion of Vpr-deregulated genes in primary CD4+ T cells controlled by NFAT.
• To investigate if Vpr-mediated NFAT activation is conserved across different HIV-1 clades (M, N, O, P).
• To elucidate how Vpr-mediated NFAT activation contributes to HIV-1 pathogenesis and replication.

Main Methods:

• RNA sequencing and transcription factor network analyses of primary CD4+ T cells infected with HIV-1 (intact vs. defective vpr).
• Analysis of Vpr proteins from diverse HIV-1 groups (M, N, O, P) for NFAT activation.
• Quantitative real-time PCR to confirm Vpr-mediated gene expression changes.

Main Results:

• Vpr significantly alters the transcriptome of CD4+ T cells, with NFAT controlling 46.5% of deregulated genes.
• Vpr upregulates immune signaling and proliferation pathways while downregulating cell cycle and ribosome activity.
• NFAT inhibition abrogated Vpr-enhanced HIV-1 replication and alleviated G2 arrest, confirming NFAT's critical role.

Conclusions:

• A significant portion of Vpr-induced transcriptional changes in CD4+ T cells are NFAT-dependent.
• Vpr-mediated NFAT activation reprograms the host cell transcriptome to favor HIV-1 replication.
• These findings highlight NFAT as a key regulatory event in HIV-1 pathogenesis.