The Public Mucosal Antibody Repertoire in HIV-1 Infection

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.