# Role of Type I IFNs in Mucosal HIV-1 Immunity and Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $549,857

## Abstract

ABSTRACT
The gut is a major site for early HIV-1 infection and CD4+ T cell depletion, and a critical compartment for the
antiviral action of the type I interferons (IFN) that include the 12 IFNα subtypes and IFNβ. However, the initial
IFN response may be suboptimal, as transmitted/founder (TF) HIV-1 strains still manage to break through.
Using next-generation sequencing, we reported that the IFNα subtypes expressed by plasmacytoid dendritic
cells (pDCs) following HIV-1 exposure ex vivo had relatively weak antiviral activity. These weakly antiviral IFNα
subtypes include IFNα2, the only IFNα subtype approved for clinical use, and IFNα1, a potential antagonist of
type I IFN signaling. To date, in-depth studies on the regulation and biological properties of the IFNα subtypes
and IFNβ in primary pDCs and gut cells has not yet been undertaken. Paradoxically, the type I IFNs were also
linked to chronic immune activation, a strong predictor of HIV-1 disease progression. The phenotype is likely
due to the immunomodulatory properties of the type I IFNs, but the exact mechanisms remain unclear. Of note,
gut barrier dysfunction occurs early in HIV-1 infection, leading to the translocation of microbes into the lamina
propria, resulting in immune activation. We reported that gram-negative commensal bacteria enriched in the
gut mucosa of HIV-1-infected individuals enhanced HIV-1 replication and CD4+ T cell death ex vivo in the gut
Lamina Propria Aggregate Culture (LPAC) model. Here, we hypothesize that the transition from a
protective to a pathogenic role for type I IFNs may be driven by translocating enteric microbes.
Microbial exposure may raise the threshold for the antiviral effects of type I IFNs to manifest and `license'
immunomodulatory ISGs to promote myeloid (mDC) activation/trans-infection and CD4+ T cell infection/
apoptosis. These microbe-driven pathogenic effects of type I IFNs may be sustained during chronic infection.
Interestingly, we observed that type I IFN responses during chronic HIV-1 infection are compartmentalized in
vivo, with differentially enhanced IFNα versus IFNβ in the blood versus the gut, respectively. To date, the
cellular sources and mechanisms driving the elevated type I IFN signature in the gut remains unknown. We
thus propose to investigate the role of type I IFNs in gut HIV-1 infection during the acute stage, at the onset of
microbial translocation, and during the chronic stage. In Aim 1, we will evaluate the regulation, anti-HIV-1
activity and functional properties of the IFNα subtypes and IFNβ. In Aim 2, we will determine how type I IFNs
modulate mDC activation and T cell function/survival in the context of HIV-1-associated gut dysbiosis and
microbial translocation. In Aim 3, we will determine the source and triggers of abnormal type I IFN signature
during chronic infection using gut tissues from uninfected, untreated HIV-1-infected and HIV-1-suppressed
individuals. The results should provide urgently needed insights on ho...

## Key facts

- **NIH application ID:** 10143180
- **Project number:** 5R01AI134220-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mario Luis Santiago
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $549,857
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143180

## Citation

> US National Institutes of Health, RePORTER application 10143180, Role of Type I IFNs in Mucosal HIV-1 Immunity and Pathogenesis (5R01AI134220-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10143180. Licensed CC0.

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