# Structural Biophysics of HIV Splicing and Transcriptional Control

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $352,473

## Abstract

Project abstract: Despite advances in antiretroviral therapy, HIV continues to pose serious threats to human
health and global economies. Knowledge gaps in understanding the basic mechanisms that control HIV gene
expression present critical barriers to identifying novel targets for therapeutic intervention or strategies to coun-
teract viral latency. In this proposal, we endeavor to close those gaps concerning the contributions of RNA struc-
tural dynamics to HIV splicing and transcriptional control. We posit that HIV uses structured RNA elements to
direct the cooperative assembly of specific RNA-protein (RNP) complexes that in turn modulates splicing. This
type of RNA-mediated cooperativity is an innovative concept that explains why HIV conserves RNA structures
near its splice sites. Those structures and its conformational dynamics can either positively or negatively impart
cooperative protein-protein interactions; we seek to understand the biophysical nature of such mechanisms. We
present strong evidence that the RNA interactions surrounding HIV splice sites A2 and A3 intrinsically regulate
the levels of vpr and tat, respectively. Mutations within those RNA structures inhibit HIV replication by deregu-
lating RNA splicing. We further contend that similar RNA-mediated cooperative mechanisms determine the ex-
tent to which the cellular P-TEFb is released from 7SK snRNA and made available to stimulate HIV transcription
elongation. To test the extent to which RNA-mediated cooperativity influences HIV nuclear gene expression, we
have developed a technically innovative research program that integrates cutting edge biophysical and biochem-
ical techniques to extract mechanistic principles about host-virus RNP complexes. We will implement this pro-
gram by adopting two broadly conceptual specific aims: 1. Molecular interactions of viral RNAs and RNPs that
contribute to HIV splicing and 2. Molecular interactions of 7SK snRNA and its different RNPs that contribute to
HIV transcription. The success of this proposal promises to deliver unprecedented in-sights into the structural
dynamics of RNA-RNA and protein-RNA interactions that control HIV gene expression and it may inform on
details into molecular mechanisms that contribute to latency. This will in turn provide a foundation for identifying
novel targets for cure strategies.

## Key facts

- **NIH application ID:** 10034853
- **Project number:** 9R01AI150830-06A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Blanton Smith Tolbert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,473
- **Award type:** 9
- **Project period:** 2020-08-19 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034853

## Citation

> US National Institutes of Health, RePORTER application 10034853, Structural Biophysics of HIV Splicing and Transcriptional Control (9R01AI150830-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10034853. Licensed CC0.

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