Glycomic modulation of inflammaging and immune functions during HIV infection
Active Project Grant Awarded Last action
- Award ID
- R01AG092241
- Recipient
-
Northwestern University UEI KG76WYENL5K1
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,486,696
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date 36% complete
- Place of performance
- Chicago, IL 60611, USA
Award details come from USAspending.gov.
Description
- Abstract
- There is an urgent need to identify biomarkers that can predict the development of inflammation-associated comorbidities in people with HIV (PWH) on antiretroviral therapy (art), as well as to develop novel strategies to prevent or treat these comorbidities. Our recent data suggest that glycomic alterations in circulating iggs are not only candidates for such biomarkers but they may also mechanistically contribute to HIV-associated inflammation by compromising antiviral immuity in a manner that can be normalized in the general population, IGG glycomic alterations drive inflammatory responses during aging (INFLAMMAGING). In a recent publication (giron ET AL., nature communications, 2024), we found that living with art-suppressed HIV infection is associated with an acceleration in the accumulation of pro-aging IGG glycomic alterations. Specifically, antibodies from PWH on art showed a significant loss of the anti-inflammatory glycans galactose (AGALACTOSYLATION) and sialic acid (HYPO-SIALYLATION) compared to HIV-negative controls. These alterations were associated with greater inflammation and increased severity of INFLAMMAGING-associated comorbidities in PWH on art. In proof-of-concept studies, we also found that these alterations might precede the development of such comorbidities by years, making them viable candidates for discovering predicitive biomarkers. Beyond their potential as biomarkers, AGALACTOSYLATION and HYPO-SIALYLATION could also constitute causative mechanisms contributing to inflammation in PWH on art: 1) AGALACTOSYLATION: glycans on iggs regulate the binding of iggs to their FC receptors, defining the ability of iggs to elicit anti-viral innate immune functions. We examined whether the lack of galactose on iggs compromised their anti-HIV FC-mediated immune functions; we glyco-engineered the HIV antibody 10-1074 to produce agalactosylated and highly-galactosylated glycoforms. Agalactosylated glycoforms exhibited significantly lower anti-HIV immune function than highly-galactosylated glycoforms. We propose that this compromised anti-HIV immune function, caused by IGG AGALACTOSYLATION, impairs the immune system's ability to control virally-infected cells, leading to greater inflammation. Consistent with this hypothesis, we found IGG AGALACTOSYLATION during art correlated with elevated levels of HIV DNA during art and faster HIV viral rebound after stopping art. 2) HYPO-SIALYLATION: sialic acid can initiate an anti- inflammatory response by binding to inhibitory molecules on myeloid cells. Loss of sialic acid hinders this mechanism. Our data support this mechanism by showing that treating humanized mice (no art) with sialidase inhibitors (to prevent HYPO-SIALYLATION and preserve sialic acid) attenuated viremic HIV-associated inflammation. These data support our overarching hypothesis that AGALACTOSYLATION and HYPO-SIALYLATION: 1) can serve as predictive biomarkers for INFLAMMAGING-associated comorbidities in PWH on art (aim 1); 2) are mechanistically linked to HIV persistence and inflammation by compromising anti-viral FC-mediated innate immune functions (aim 2A, 2B); and 3) can be normalized to enhance immunity and inhibit INFLAMMAGING (aim 2B, aim 3).
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $50,503 | |
| Amendment | $454,532 | |
| Amendment | $454,532 | |
| Original award | $527,129 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| President And Fellows Of Harvard College | $39,250 | |
| The Wistar Institute Of Anatomy And Biology | $48,915 |
Quick answers
Who received award R01AG092241?
R01AG092241 was awarded to Northwestern University by National Institute on Aging (National Institutes of Health) on January 15, 2025.
How much is award R01AG092241 worth?
$1,486,696 has been obligated on R01AG092241.
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