# Immune exhaustion in perinatal HIV infection

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $120,016

## Abstract

PROJECT SUMMARY
Globally over 2 million children live with HIV and 400 are newly infected every day. There is an urgent need for
an HIV cure and one barrier to that is immune exhaustion. The goal of our study is to determine the role of
immune exhaustion in pediatric HIV pathogenesis in order to guide innovative approaches toward a functional
cure. Exhausted T cells are defined by progressive loss of proliferative, cytotoxic, and cytokine immune
responses mediated by the sustained upregulation of multiple inhibitory receptors (IR). Our prior research in a
cohort of Kenyan children with perinatal HIV infection demonstrates that HIV+ children have high levels of
inhibitory receptor PD-1 on T cells that correlate with HIV disease progression. Moreover, high PD-1 levels
predicted lower HIV-specific proliferative responses suggesting that high PD-1 levels may weaken HIV
eradication or functional cure strategies. There are several other IRs – including CD160, lymphocyte activation
gene 3 (LAG3), cytotoxic T lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin domain and mucin domain-
containing protein 3 (TIM3), and T-cell immunoreceptor and Ig and ITIM domains (TIGIT) that also dampen
immune responses in HIV+ adults. Simultaneous upregulation of multiple IRs links to increasing degrees of
immune dysfunction, yet the levels of IRs on T cells and their functional consequences in children with perinatal
HIV infection is unknown. The objective of this study is to perform a comprehensive analysis of immune
checkpoints including their phenotypic expression, transcriptome, and functional potential in HIV+ children. We
will utilize a biobank of peripheral blood mononuclear cells from the Pediatric Immune Activation Study led by
Dr. Khaitan that includes 160 children with perinatal HIV infection and 82 HIV-unexposed uninfected controls
between ages 2 months to 20 years for this study. We hypothesize there is a unique signature of multiple IR
coexpressions on CD4 and CD8 T cells in children with perinatal HIV infection that identifies truly exhausted T
cells. Our specific aims are to (1) Determine the phenotype and transcriptome of IR-expressing T cells in children
with perinatal HIV infection; and (2) Determine the functional consequences of IRs on CD4 and CD8 T cells and
potential for reversal in perinatal HIV infection. In Aim 1 we will apply innovative technologies of 30-parameter
flow cytometry and single cell RNA genomic sequencing to extract detailed immunologic and transcriptomic data
from limited PBMC numbers obtained from children. In Aim 2 we will determine ex vivo proliferative, cytotoxic,
and cytokine responses to HIV peptides and childhood vaccines and in vitro responses to IR inhibitors. Our
research will fill fundamental knowledge gaps in understanding the role of immune exhaustion in pediatric HIV
pathogenesis, with potential to identify novel targets for future HIV functional cure strategies in children.

## Key facts

- **NIH application ID:** 10135131
- **Project number:** 5R21HD102871-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Alka Khaitan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,016
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135131

## Citation

> US National Institutes of Health, RePORTER application 10135131, Immune exhaustion in perinatal HIV infection (5R21HD102871-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135131. Licensed CC0.

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