# HIV-1 Vpr disrupts the IFN-TET-ISG pathway to promote HIV-1 infection and persistence

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $270,394

## Abstract

PROJECT SUMMARY
The long-term goal of this investigation is to elucidate the mechanisms by which HIV-1 accessory protein Vpr
alters host defense pathway to enhance HIV-1 persistent infection and pathogenesis. This investigation is
proposed based on five key findings we made recently. (1) HIV-1 infection induces efficient production of type I
interferons (IFN-I) by activating pDC, which fails to control HIV-1 infection but rather contributes to HIV-1
diseases. (2) HIV accessory protein Vpr plays an important role to counteract the effect of IFN-I to promote
HIV-1 infection. (3) TET methylcytosine dioxygenases are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1
(CRL4VprBP) E3 ligase which promotes TET binding to chromatin. (4) TET2 is recruited by sequence-specific
transcription factors (TFs) to and activates the expression of specific target genes, including a subset of
interferon (IFN)-stimulated genes (ISGs) and viral-defense genes. (5) Vpr interacts with both VprBP and TET
and reprograms CRL4VprBP ligase to catalyze polyubiquitylation of TET2, resulting in TET2 degradation and
inhibition of TET2-mediated induction of ISGs, including three HIV restriction factors.
We propose that there exists an IFN-JAK-STAT-TET-ISG pathway that modulates IFN signaling and the
expression of a subset of ISGs. The Vpr-mediated degradation of TET disrupts this pathway and counteracts
the anti-HIV effect of IFN in human cells but not the IFN induction pathway, thereby promoting HIV-1 infection
and persistence in the presence of IFN-I, which contributes to HIV-induced inflammation and pathogenesis.
We propose four specific aims to test this hypothesis. Aim 1 will determine the function and mechanism Vpr-
mediated TET degradation. Aim 2 is to determine the mechanism of the IFN-JAK-STAT-TET-ISG pathway.
Aim 3 will study how Vpr and the IFN-STAT-TET pathway modulate HIV-1 infection and persistence in vivo,
including the establishment and rebound of HIV-1 reservoir during cART. Aim 4 will investigate how Vpr
disrupts the IFN-TET pathway to contribute to HIV-induced inflammation and T cell depletion/impairment.
Combining the expertise of the two PIs in HIV virology and immunology, ubiquitin pathway and TET-mediated
epigenetic control and motivated by a series of recent key findings, this investigation will establish the IFN-
JAK-STAT-TET-ISG pathway in HIV-1 target cells and determine how Vpr disrupts this pathway to lead to
persistent HIV infection and the HIV-associated inflammation. This investigation will also gain insights into DNA
de/methylation as a mechanism in dynamic gene regulation and immune response, identify novel viral and host
targets for developing HIV-1 “cure” treatments, and establish a paradigm on how this novel pathway is involved
in the general anti-viral mechanism against other human viruses.
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## Key facts

- **NIH application ID:** 10015198
- **Project number:** 5R01AI127346-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lishan Su
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $270,394
- **Award type:** 5
- **Project period:** 2016-06-15 → 2020-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015198

## Citation

> US National Institutes of Health, RePORTER application 10015198, HIV-1 Vpr disrupts the IFN-TET-ISG pathway to promote HIV-1 infection and persistence (5R01AI127346-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10015198. Licensed CC0.

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