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 IFN? subtypes and IFN?. 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 IFN? subtypes expressed by plasmacytoid dendritic cells (pDCs) following HIV-1 exposure ex vivo had relatively weak antiviral activity. These weakly antiviral IFN? subtypes include IFN?2, the only IFN? subtype approved for clinical use, and IFN?1, a potential antagonist of type I IFN signaling. To date, in-depth studies on the regulation and biological properties of the IFN? subtypes and IFN? 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 IFN? versus IFN? 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 IFN? subtypes and IFN?.
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 how type I IFNs impact HIV-1 pathogenesis that may inform strategies to either harness these antiviral cytokines for curative strategies or block their immune effects to reduce chronic inflammation.

Public Health Relevance

Understanding the mechanism(s) underlying the protective and pathological role of IFN? in mucosal HIV-1 infection could direct the development of novel interferon-based antiviral therapies against HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI134220-01
Application #
9409646
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Lawrence, Diane M
Project Start
2017-05-01
Project End
2022-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Dillon, Stephanie M; Guo, Kejun; Austin, Gregory L et al. (2018) A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis. AIDS 32:1599-1611
Yoder, Alyson C; Guo, Kejun; Dillon, Stephanie M et al. (2017) The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria. PLoS Pathog 13:e1006226