# Discovery and Mechanism of Antiretroviral Factors

> **NIH NIH R37** · ROCKEFELLER UNIVERSITY · 2020 · $505,959

## Abstract

We have succeeded in identifying a number of genes with antiretroviral activity, and the continuation of this
project will naturally progress with a detailed examination of the mechanism of action of one validated
restriction factor (Mx2) in Aim 1, and a more broadly based follow up of additional hits, as well as additional
ISG screening in Aim 2.
In Aim 1 we will build on our discovery that Mx2 is an antiretroviral protein by determining its mechanism of
action. Mx2 inhibits HIV-1 infection in a capsid dependent manner at a step between reverse transcription
and integration. A few potential mechanisms might underlie this activity. First, Mx2 might directly target the
incoming viral capsid, in a manner akin to the TRIM5a and Fvl antiretroviral proteins Crucially, we have
found a number of amino acids in CA that when mutated confer resistance to Mx2 antiviral activity. These
will serve as key specificity controls in our binding and core-fate assays. Additionally, we will determine
whether Mx2 binds to nuclear transport components, whether the nature of the Mx2 nuclear targeting signal
is important for its antiviral activity and whether the route taken by HIV-1 into the nucleus affects its
susceptibility to Mx2. Ultimately these experiments should determine how Mx2 functions and whether capsid
recognition and/or specific nuclear entry pathway occlusion is responsible.
Our ISG screening platform has revealed numerous (-30) candidate antiretroviral proteins that either protect
cells from infection, or reduce the yield of infectious virons from ISG expressing cells. Currently, our analysis
of these hits is at various stages of follow up. In Aim 2 we will follow the same paths exemplified by our
previous work on Mx2 and CNP. Ultimately, we will aim to determine precisely how these ISGs inhibit
reroviral replication, and crucially whether they are required for the full antiviral activity of interferon. Finally,
we are screening additional ISGs that were not present in our originally constructed libraries. Again the path
taken by these studies will mirror our previously successful approaches.
 RELEVANCE (See instructions):
 Mammals, including humans, have an array of antiviral defense mechanisms. The mechanism by which
these antiviral defenses work is only beginning to be understood. Identifying and understanding the
 mechanism of action of antiretroviral gene products could lead to completely new chemotherapeutic
 strategies for tackling infectious diseases, including AIDS.

## Key facts

- **NIH application ID:** 9848491
- **Project number:** 5R37AI064003-15
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Paul D. Bieniasz
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,959
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848491

## Citation

> US National Institutes of Health, RePORTER application 9848491, Discovery and Mechanism of Antiretroviral Factors (5R37AI064003-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9848491. Licensed CC0.

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