# Epigenetic modification of HIV-1 Cap

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $696,828

## Abstract

Project summary
Basic research opens the door to better understand, treat, and ultimately prevent existing and
emerging public health threats. NIAID has prioritized fundamental research into underpinnings of
the HIV-associated chronic immune activation despite the control of viral load by daily
antiretroviral medication. Recent findings of the HIV-1 RNA cap hyper methylation reveal a new
paradigm of viral RNA regulation that finely tunes viral gene expression for adaptive and sustained
virus replication in host immune cells. Revealing preliminary research on a new generation of HIV
drug, which compromises replication of HIV clinical isolates without positive selection for drug
resistance, has exposed inhibition of host TGS1 hypermethylation of HIV-1 m7G-Cap on RRE-
containing RNAs, thus establishing this small molecule will be a powerful molecular probe to
investigate the molecular interactions that regulate HIV cap hypermethylation. The HIV intron-
containing (ic)RNA, which contains RRE, has been reported to trigger innate immune signaling in
myeloid cells, and the communications induce T cell markers of exhaustion. Preliminary data posit
the hypothesis icRNA is distinguished by its TMG-Cap, which hosts use to alleviate excessive
innate immune signaling. However, it remains poorly understood how the Rev/RRE on the 3’- of
viral RNA participates in the cap hyper methylation on the 5’- end. Now, by integrating ample
preliminary cryoEM studies, HIV RNA-protein co-precipitations, and documentation of the
specialized translation pathway licensed by the hypermethylated HIV-1 m7G-Cap, we propose an
innovative and breakthrough model that explains previous controversial observations and unclear
mechanism of Rev/RRE functionality at the 5’-end of HIV-1 RNA and in translation control.
Specifically, host RNA helicase A (RHA) homo-dimerizes upon binding cognate RNA structures
in the HIV-1 RNA through bipartite arrangement that tethers Rev/RRE in proximity to nuclear cap
binding complex. Interdisciplinary tools are employed to delve into the basic science of the HIV
TMG-Cap pathway linked to Rev/RRE. Our preliminary results posit that dysregulating the TMG-
Cap pathway triggers host innate immune signaling leading to outcomes that are advantageous
for the host. The overarching project goal is to define the structural basis of the HIV cap
hypermethylation regulation for viral post-transcriptional control of gene expression and define its
linkage with HIV’s ability to modulate host innate immune signaling. At the project completion, the
new information is expected to arm scientists for developing next-wave treatments to neutralize
deleterious immune signaling in HIV-immune cell environments.

## Key facts

- **NIH application ID:** 11014754
- **Project number:** 1R01AI184293-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Kathleen A. Boris-Lawrie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $696,828
- **Award type:** 1
- **Project period:** 2024-08-14 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11014754

## Citation

> US National Institutes of Health, RePORTER application 11014754, Epigenetic modification of HIV-1 Cap (1R01AI184293-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11014754. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*