# Elucidating antiviral defenses against diverse immunodeficiency viruses using a novel, high-throughput CRISPR/Cas9 screening method.

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $51,036

## Abstract

PROJECT SUMMARY
The zoonotic transmission of viral pathogens from animals to humans contributes to the majority of emerging
infectious diseases, which pose a substantial and increasing threat to human health. While host innate
immunity—namely the production of Type I Interferon (IFN) and the subsequent production of Interferon
Stimulated Genes (ISGS) with antiviral activities—plays an important role in determining viral tropism and limiting
the cross-species transmission of viruses, much work remains on identifying and characterizing ISGs limiting
viral tropism. Our lab has determined that while the human immunodeficiency virus (HIV-1) and non-human
primate simian immunodeficiency viruses (SIV) are able to at least partly evade IFN-mediated defenses in cells
from their cognate host, they remain exquisitely sensitive to such defenses in cells from unnatural hosts. Since
HIV-1 and HIV-2 both arose from the cross-species transmission of diverse SIV species, the human and primate
immunodeficiency viruses are a rich model system for studying the relationship between host innate immunity
and viral adaptation. In order to identify human genes inhibiting SIV infection, we have modified a recently
described high-throughput, CRISPR-based screening assay to identify human ISGs with activity against
SIVmac239. Our preliminary data suggests that our model system is working as designed, as had identified a
number of candidate genes that inhibit SIVmac infection in human cells. In Aim 1, we will determine the
mechanism of action of novel ISGs with confirmed activity against SIVmac239. We will perform stepwise
mechanistic studies to dissect the point of inhibition in the viral lifecycle. We will additionally perform co-
immunoprecipitation and co-localization studies to identify viral components and cellular cofactors relevant to
mechanism of inhibition. In Aim 2, we will use our established pipeline to screen for ISGs inhibiting diverse
SIV strains. Preliminary data strongly suggests that we will be able to directly use the system we have developed
to screen diverse strains of SIV. We will assess multiple SIV strains for sensitivity to IFN and screen those that
are sensitive for inhibitory ISGs. We hypothesize that there will be both conserved and distinct inhibitory factors
targeting the various SIV species. Combined, these approaches will reveal novel restriction factors that inhibit
diverse SIVs in human cells, providing insight into the evolutionary adaptations that HIV-1 and HIV-2 made in
order to successfully colonize humans.

## Key facts

- **NIH application ID:** 10160258
- **Project number:** 1F30AI157898-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Daniel Poston
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2020-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160258

## Citation

> US National Institutes of Health, RePORTER application 10160258, Elucidating antiviral defenses against diverse immunodeficiency viruses using a novel, high-throughput CRISPR/Cas9 screening method. (1F30AI157898-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10160258. Licensed CC0.

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