# Host genetic predictors of plasma IL-1b levels and pharmacogenomics of in vivo IL-1b blockade during treated HIV disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $804,532

## Abstract

PROJECT SUMMARY/ ABSTRACT
Despite effective antiretroviral therapy (ART), HIV-infected individuals have reduced life expectancy and a
higher incidence of aging-associated diseases compared to HIV-uninfected controls. Persistent systemic
inflammation despite suppressive ART has been associated with serious non-AIDS morbidity (e.g., myocardial
infarction, stroke, malignancy) and mortality. Recent data suggests that an upstream regulator of interleukin
(IL)-6, interleukin-1 beta (IL-1β), may be the major driver of increased cardiovascular risk observed in HIV+
ART-suppressed individuals. The recent CANTOS trial has now demonstrated in over 10,000 individuals that in
vivo IL-1β blockade with the monoclonal antibody canakinumab significantly reduced cardiovascular events
and cancer mortality in the general population. We have recently performed a phase 1 trial administering a
single dose of canakinumab to HIV+ ART-suppressed participants and found that in vivo IL-1β blockade led to
significant reductions in plasma IL-1β (as well as associated systemic inflammatory markers plasma IL-6 and
high sensitivity C-reactive protein), vascular inflammation, and monocyte activation. Furthermore, our ex vivo
data suggests that IL- β plays a critical role in maintaining the “HIV reservoir” (the total amount of residual virus
that persists during ART suppression and potentially drives systemic inflammation). We will use an unbiased
integrated approach that combines several high dimensional datasets to test the hypothesis that IL-1β triggers
the proinflammatory response that fuels HIV immune dysfunction and persistence. Our proposed study will be
the first (in HIV+ or HIV-uninfected individuals) to pursue the link between host genetics and plasma IL-1β
levels – while simultaneously assaying several proinflammatory cytokines in this pathway, including IL-6 and
IL-18. In Aim 1 we will identify DNA variants associated with plasma IL-1β in 1,000 HIV+ ART-suppressed
participants from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort using
custom whole exome sequencing to add to existing genomewide array data. Individuals with extreme
phenotypes (highest and lowest deciles of plasma IL-1β levels) will then be selected for functional validation in
Aim 2 using a novel approach that simultaneously characterizes RNA and protein expression at single cell
resolution using single cell RNA and antibody sequency (scRNA-Abseq). Finally, we will perform functional in
vivo validation of identified genes associated with IL-1β signaling, leveraging samples from our phase 1 trial of
canakinumab in Aim 3. Therefore, we will functionally validate findings from Aim 1 as well as identify novel
genes/pathways by studying individuals with unique HIV+ phenotypes (extreme plasma IL-1β levels and after
canakinumab treatment, respectively) in Aims 2 and 3. The proposed work will identify specific genes and
immune pathways that may act synergistically with IL-1β, i...

## Key facts

- **NIH application ID:** 10170232
- **Project number:** 5R01AI143464-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sulggi Angela Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $804,532
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170232

## Citation

> US National Institutes of Health, RePORTER application 10170232, Host genetic predictors of plasma IL-1b levels and pharmacogenomics of in vivo IL-1b blockade during treated HIV disease (5R01AI143464-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170232. Licensed CC0.

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