# The Public Mucosal Antibody Repertoire in HIV-1 Infection

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $210,600

## Abstract

PROJECT SUMMARY
Restoring the integrity of the gastrointestinal tract could be key to counteracting the spectrum of inflammation-
associated debilitating illnesses and increased mortality among persons living with HIV-1 (PWH) on antiretroviral
therapy. This may be accomplished by harnessing pathways that maintain gut homeostasis, of which IgA-
microbiome interactions are emerging as fundamental mechanisms. In fact, using gut biopsies from an age/sex-
matched cohort of PWH and HIV-1-uninfected individuals, we demonstrated alterations in the IgA repertoire
among PWH that associated with specific bacterial taxa. Testing these IgA-microbiome correlations
experimentally is a major challenge, as the human antibody repertoire is extremely diverse, with over a trillion
distinct antibodies possible. Interestingly, recent high-throughput studies revealed the existence of 'public'
antibodies: clonotypes that were shared among unlinked individuals that encode the same V and J genes and
highly related CDR3 antigen-binding regions. The biology of public antibodies remains mysterious; statistically,
these antibodies should not exist unless there is a shared antigenic history and/or evolutionarily-conserved
function. Notably, in inbred, specific-pathogen-free mice, a subset of public IgA interacted with the gut
microbiome, suggesting a potential role in gut homeostasis. To date, whether these findings extend to humans
remains unclear. Using our next-generation sequencing dataset, we uncovered over a dozen public IgA
clonotypes specific to PWH versus HIV-1-uninfected controls, and vice versa. As a critical first step in
understanding their biology, our main goal in this exploratory study is to prepare recombinant public IgA
clonotypes specific to HIV-1-uninfected individuals or PWH, and interrogate their reactivity against fecal bacterial
communities and microbial glycans. We will then test if bacteria-reactive public IgA recovered from PWH gut
biopsies influence HIV-1-mediated CD4+ T cell death and inflammation in a robust ex vivo Lamina Propria
Aggregate Culture model that we developed previously. These studies promise to provide the field with a first
look at the nature and immune properties of public IgA clonotypes in the human gastrointestinal tract, that may
provide promising leads for therapeutic modulation of mucosal inflammation in chronic HIV-1 infection and a
wide variety of medical conditions associated with a 'leaky gut' syndrome.

## Key facts

- **NIH application ID:** 10918746
- **Project number:** 1R21AI183981-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mario Luis Santiago
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $210,600
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918746

## Citation

> US National Institutes of Health, RePORTER application 10918746, The Public Mucosal Antibody Repertoire in HIV-1 Infection (1R21AI183981-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10918746. Licensed CC0.

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