# Retroviral infection and new modulators of the MHCII pathway

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $799,185

## 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 a positional cloning approach, we 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 potent 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 these
variants were genetically linked to the differential outcomes of hepatitis B and C viral infections in humans
which are controlled by neutralizing Ab responses.
 The process of loading of MHCII molecules with high-affinity, pathogen-derived peptides is mediated by
the interaction of MHCII with another non-polymorphic MHCII-like molecule, H2-M (HLA-DM in humans). 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 direct
competition between H2-O/DO and MHCII for interaction with H2-M/DM was incomplete, because at least 2
mouse Ob, as well as some human DOa and DOb variants result in H2-O/DO molecules, which bind to H2-
M/DM but fail to inhibit its function. Clearly, there are gaps in our knowledge of the mechanism by which H2-
O/DO negatively regulates MHCII presentation, a process that is central to controlling adaptive immune
responses. Using positional cloning in the mouse and a biochemical approach, novel modulators of the MHCII
pathway which have not been previously described were identified. We propose to study how these new
modulators regulate Ag presentation by H2-O to direct potent virus-neutralizing antibody responses.

## Key facts

- **NIH application ID:** 10800897
- **Project number:** 1R01AI175279-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Tatyana V Golovkina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $799,185
- **Award type:** 1
- **Project period:** 2024-06-12 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800897

## Citation

> US National Institutes of Health, RePORTER application 10800897, Retroviral infection and new modulators of the MHCII pathway (1R01AI175279-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10800897. Licensed CC0.

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