# New retroviral restriction factor

> **NIH NIH R56** · UNIVERSITY OF CHICAGO · 2021 · $776,245

## Abstract

Abstract
Select humans and animals are able to control persistent viral infections via adaptive immune responses that
include the development of neutralizing antibodies (Abs). However, the mechanisms underlying these
exceptional protective responses remain largely unknown. Using positional cloning approach, we have
identified a gene responsible for virus-neutralizing Ab responses in mice from the I/LnJ strain following
infection with two distinct retroviruses, Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus
(MuLV). This gene is H2-Ob (Ob), which encodes the b subunit (H2-Ob) of the ab obligate heterodimer H2-O.
H2-O (DO in humans), is a non-classical Major Histocompatibility Class II (MHCII)-like molecule and a known
negative regulator of the MHCII antigen presentation pathway. The recessive loss-of-function I/LnJ Ob allele
allowed for the production of potently neutralizing Abs in infected mice. Subsequent bioinformatics and
functional analyses of the human homologues - DOa and DOb - revealed both loss- and gain-of-function
variants, several of which were genetically linked to the differential outcomes of hepatitis B and C viral
infections in humans.
 The process of loading of MHCII molecules with peptides is mediated by the interaction of MHCII with
another non-polymorphic MHCII-like molecule, H2-M (HLA-DM in humans), which loads MHCII molecules with
high-affinity, pathogen-derived peptides. H2-M function is opposed by H2-O, which acts as an MHCII mimic,
binding to H2-M and blocking its ability to catalyze MHCII peptide loading. Importantly, our studies showed that
this accepted paradigm of a direct competition between H2-O/DO and MHCII for binding to H2-M/DM was
incomplete, because I/LnJ Ob, as well as some human DOa and DOb variants result in H2-O/DO molecules,
which fail to inhibit peptide loading of MHCII and yet retain the ability to interact with H2-M/DM. Clearly, there
are severe gaps in our knowledge of how H2-O/DO negatively regulates MHCII presentation, a central process
directing effective immune responses.
 The studies in this renewal application seek to address these gaps. Specifically, Aim1 will elucidate the
mechanism underpinning the loss of inhibition of H2-M function by the mutant H2-O found in I/LnJ mice as a
means to understand how H2-O normally functions. Aim 2 seeks to discover novel genes involved in the
regulation of the H2-O-dependent control of MHCII peptide loading and Aim 3 will determine how two different
viruses (a retrovirus and a gherpesvirus) exploit H2-O regulation to suppress the anti-viral immune response
and/or to promote viral pathogenesis.

## Key facts

- **NIH application ID:** 10441970
- **Project number:** 2R56AI117535-06A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Tatyana V Golovkina
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $776,245
- **Award type:** 2
- **Project period:** 2015-11-13 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441970

## Citation

> US National Institutes of Health, RePORTER application 10441970, New retroviral restriction factor (2R56AI117535-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10441970. Licensed CC0.

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