# Hosts Going Viral: Building The Tools And Systems To Determine How Human-Relevant Biology Evolved Through The Capture Of Viral Genes In Our Distant Ancestors

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $397,500

## Abstract

SUMMARY:
Acquiring extracellular genetic and functional novelty can forever change the evolutionary trajectory of
organisms, from mitochondria to antibiotic resistance to placental formation. Retroviruses heritable through the
germline, endogenous retroviruses (ERVs), comprise eight percent of the human genome (four times more than
protein coding sequence). The vast majority of ERVs lack all protein coding potential. A select few ERV genes
have been preserved over evolutionary timescales, a strong indication that these specific genes are beneficial.
env is the most frequently preserved ERV gene. In retroviruses, env encodes a glycoprotein that interacts with
specific cellular receptors and is the virus-cell membrane fusogen. These activities have been repurposed by a
pair of ERV envs that form the syncytiotrophoblast, an essential placental structure of fused cells at the maternal-
fetal interface. Divergent envs have been coopted by different mammalian lineages for the same function.
Knowledge of how ERV genes are acquired and repurposed is largely restricted to DNA and mRNA, while it is
typically the proteins that carry out their functions. A dearth of quality reagents for ERV proteins has impeded
our ability to define when, where, and why these proteins are expressed. We will leverage our expertise as
evolutionary biologists, protein biochemists, and B cell immunologists to move ERV research into the proteome
by generating, quality controlling, and disseminating the reagents required for this transition. Our primary focus
is EnvP(b)1, an env preserved for >40 million years with no known function. Evolution has maintained its
membrane fusion activity across human, ape and monkey orthologs. Expression in cultured cells results in fused
monolayers of multinucleated cells and rapid cell death. Expression in vivo must therefore be tightly regulated,
and its activity tailored to its function. We find genetic and functional evidence of evolutionary refinement of
EnvP(b)1 over the past >40 million years. We will, in vitro, define the tissue and species specificities of membrane
fusion by human and non-human primate (NHP) EnvP(b)1 orthologs. Using ancestral reconstruction, we will
determine how EnvP(b)1 function evolved to its present form across primate lineages. Given its cytotoxicity and
ability to produce cells with variable chromosomal content, the preservation of EnvP(b)1 indicates it must perform
critical functions. We will define the anatomical sites and context of EnvP(b)1 protein expression in humans and
NHPs, and if cell-cell fusion occurs at these sites. This work will ultimately establish NHP models required to
define the function and explain why EnvP(b)1 is maintained. Using a carefully controlled antibody reagent, we
find EnvP(b)1 protein expression in healthy human and NHP tissues, including placenta. The placenta, a rapidly
evolving structure, is a hotbed of functional ERV Env expression. We will develop the reagents needed to dissect
...

## Key facts

- **NIH application ID:** 10937668
- **Project number:** 1R35GM154844-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kevin Raymond McCarthy
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937668

## Citation

> US National Institutes of Health, RePORTER application 10937668, Hosts Going Viral: Building The Tools And Systems To Determine How Human-Relevant Biology Evolved Through The Capture Of Viral Genes In Our Distant Ancestors (1R35GM154844-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10937668. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*