# Center for Structural Biology of HIV RNA

> **NIH NIH U54** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $797,029

## Abstract

This Project consists of a deep analysis of the structures that form on HIV-1 RNAs in infected cells, the viral and
host proteins with which they interact, and the critical roles these structures play in HIV-1 gene expression. The
virus uses specific RNA structures to regulate gene expression, but in many cases the actual folded structures
of the RNAs and of the larger complexes they form with proteins are not yet known in any detail. We have
assembled a powerful team of investigators with the broad range of skills and expertise needed to determine the
structures, to define the essential portions of the RNAs needed for biological activity, and to unravel the
mechanism of action of the RNA-protein complexes that promote virus gene expression and replication. The
steps of the viral life cycle that we propose to examine will include: the synthesis of RNA transcripts by RNA
polymerase II elongation, as allowed by the release from arrest mediated by the Tat protein, P-TEFb subunits
and the TAR RNA; the alternative splicing of HIV-1 RNAs, as controlled by cis-acting elements at the splice sites
of the viral precursor RNA; the selective nuclear export of spliced, partially spliced and unspliced mRNAs as
controlled by Rev action at the RRE element and by nuclear pore subunits; and the translation of viral mRNAs,
including the role of the 5' cap in determining the fate of the RNAs, and the activity of the RNA hairpin at the site
of translational frameshifting in regulating expression of the long Gag-Pro-Pol precursor protein. We will study
structures of “naked” RNAs in solution, but also in the context of RNA-protein complexes as they exist in intact
infected cells. We will use powerful genetic tools and rapid readouts of gene expression to identify host factors
involved in these various processes, mutagenesis and CRISPR-based knockouts to probe the functions of these
factors and the details of their interactions with RNA. We have come to appreciate that many of the RNA
structures are highly dynamic and consist of a constellation of alternative forms – clearly true in the cases of the
TAR element, the 5' cap and 5' UTR sequence that control RNA utilization, the splicing regulatory elements, and
the translational frameshift element. Our team will apply advanced methods capable of monitoring these dynamic
rearrangements at multiple time scales. The results will break new ground in discovery, design, and optimization
of viral inhibitors targeting RNA. We initially will address all these RNA structures and their functions in the
context of the actively replicating virus in lytic growth in T cells, readily studied in culture. In addition, we are
interested in the distinctive regulation of these steps that occurs in the establishment and maintenance of latency,
a state allowing persistence of virus as transcriptionally silent proviruses. We will take advantage of a new model
of latency to define changes in the RNA structures and the way they are recognized by t...

## Key facts

- **NIH application ID:** 10505795
- **Project number:** 1U54AI170660-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ALICE TELESNITSKY
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $797,029
- **Award type:** 1
- **Project period:** 2022-06-09 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505795

## Citation

> US National Institutes of Health, RePORTER application 10505795, Center for Structural Biology of HIV RNA (1U54AI170660-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10505795. Licensed CC0.

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