# Retrovirus Structure and Assembly with Inositol Phosphates

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $392,500

## Abstract

Project Summary
Assembly of Gag into an immature virus particle is a critical step in the viral life cycle. After assembly the
immature virus particle goes through a process called maturation which is required to produce infectious virus
particles. We recently showed that the small cellular molecule, inositol hexakisphosphate (IP6) is required for
both assembly and maturation, and that decreasing IP6 levels in cells severely reduces the formation of
infectious virus. While we know have a “big picture” view of how IP6 affects HIV, there is still a great deal we
don’t understand. This proposal seeks to characterize the mechanism of IP6 induced immature assembly, how
IP6 promotes mature assembly, and if these assembly steps can be targeted by antiretrovirals. Furthermore,
preliminary work suggests that IP6 is a cofactor for other retroviruses, and so this proposal will test the
hypothesis that IP6 as a retroviral cofactor is evolutionarily conserved. Specific Aim 1 is to further
characterize how IP6 binds and promotes HIV-1 assembly and maturation. High resolution cryo-EM analysis
will be performed on IP6 assembled mature virus-like particles with and without cellular proteins that are known
to bind to the viral core in cells. The effect of maturation inhibitors Bevirimat and PF-46396, which bind to the
same region as IP6, on IP6 binding and enhanced assembly will be determined using a series of biochemical
assays. In addition, this aim will test the hypothesis that IP6 is utilized by other lentiviruses. For example,
preliminary data suggest that the Equine Infectious Anemia Virus also employs IP6 for the production of
infectious virus. Specific Aim 2 is to determine if and how IP6 is utilized by retroviruses outside of the
lentivirus genus. Preliminary data shows that the alpha retrovirus Rous sarcoma virus (RSV), and the delta
retrovirus Human T-Cell Leukemia Virus (HTLV) both utilize IP6. We will identify the site of IP6 action on both
viruses using biochemical and structural approaches. We will also screen viruses from the other retroviral
genera to determine if they also utilize IP6. Specific Aim 3 is to determine if and how IP6 related compounds
affect HIV-1 immature assembly, maturation, and mature assembly. Working with a collaborator, we will
synthesize and screen IP6-like compounds in assembly and maturation assays. This aim will help to determine
if compounds that target the IP6 binding site are a feasible antiretroviral strategy.

## Key facts

- **NIH application ID:** 9989027
- **Project number:** 5R01AI147890-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Robert A Dick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2019-08-05 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989027

## Citation

> US National Institutes of Health, RePORTER application 9989027, Retrovirus Structure and Assembly with Inositol Phosphates (5R01AI147890-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989027. Licensed CC0.

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