# Regulation of NK cell antiviral responses through alternative splicing

> **NIH NIH K01** · UNIVERSITY OF CENTRAL FLORIDA · 2023 · $175,780

## Abstract

Project Summary/Abstract
Natural killer (NK) cells have been shown to play a significant role in regulating viral infections as well as in
eliminating cancerous cells. Traditionally, NK cells are classified as members of the innate immune system
because of their ability to respond rapidly and non-specifically to infected or abnormal cells. Interestingly,
burgeoning evidence suggests NK cells may also possess peptide-specific memory responses (previously only
attributable to adaptive immunity), especially in the context of several viral infections including HIV/SIV and CMV.
How NK cells can form these adaptive responses is the subject of an emerging area in immunology research,
which also includes studying trained immunity of traditionally innate effectors like NK cells. Whether adaptive NK
cell responses are the result of epigenetic modifications as observed in trained immunity, or the product of pre-
formed polymorphic receptors like KIRs or members of the NKG2 family which interact with MHC molecules, or
yet to be discovered receptors is to be determined. Here, we propose that investigating the NK cell transcriptome
can provide insights into how infection or disease states can modulate NK cell function particularly by assessing
how changes in alternative gene splicing following infection result in NK cell dysfunction or the formation of
adaptive NK cell responses. Alternative splicing is a mechanism utilized by cells in order to produce multiple
gene products from an individual gene, by splicing exons together in various combinations, sometimes leading
to gene products with very different functions. Regulation of gene splicing is complicated, but it has been shown
that environmental changes as are seen during viral infection or disease can gene splicing patterns.
Using preliminary data from sorted NK cells in an acute SIV-infection cohort we have already identified several
candidate alternatively spliced genes that exhibit differential isoform expression following SIV infection. Of
particular interest are members of the bHLH transcription factor (TF) family due to their association with the
formation of memory responses and NK cell development. Further, in a proof-of-concept study we have shown
that NKp30 isoform expression is altered following ex vivo stimulation or even following vaccination in rhesus
macaque and in human NK cell samples. Here, I propose to identify novel gene candidates and assess the roles
of the bHLH TF splice variants and other candidate genes in rhesus macaque and human NK cells. Through this
work I aim to determine whether specific gene isoform expression impacts normal NK cell functions or the
formation of adaptive NK cell responses in vivo in rhesus macaques during acute and chronic SIV infection.
The approaches outlined in this proposal will allow me to combine my postdoctoral training in NK cell biology
with my predoctoral training assessing the role of alternative splicing in vivo in order to determine the roles th...

## Key facts

- **NIH application ID:** 10550262
- **Project number:** 7K01OD031899-03
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** Daniel Ramos Ram
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $175,780
- **Award type:** 7
- **Project period:** 2021-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10550262

## Citation

> US National Institutes of Health, RePORTER application 10550262, Regulation of NK cell antiviral responses through alternative splicing (7K01OD031899-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10550262. Licensed CC0.

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