# Protective Immune Signatures Associated with Latent TB Infection in PLHIV—Insights from an Integrative Prospective Immune Monitoring Study

## TL;DR

This study identifies immune signatures in HIV-positive individuals with latent TB that may help prevent TB reactivation.

## Contribution

The study reveals novel immune markers in HIV-positive individuals with latent TB that distinguish them from those with active TB.

## Key findings

- HLTBI+ individuals showed lower T-cell activation and PD-1 expression before ART initiation.
- TB-specific TNF-α production in HLTBI+ individuals correlated with the CD4/CD8 ratio after ART.
- Distinct immune signatures, including PD-1 and TNF-α responses, were associated with latent TB in PLHIV.

## Abstract

Understanding how HIV-1 pathogenesis affects systemic and TB specific immunity in the setting of latent (LTBI+) compared to active TB infection could provide actionable insights for the prevention of reactivation. Fifty HIV-seronegative and 112 HIV-1-positive anti-retroviral therapy (ART)-naïve participants were stratified as LTBI+ (n = 35), active TB+ (n = 22) and non-coinfected (n = 55) based on an interferon gamma release assay (IGRA) and clinical confirmation prior to receiving TB therapy. Systemic and TB-specific (DosR and Rpf) immune monitoring of cellular subsets, together with multi-analyte plasma analysis, was carried out. Pursuant to isoniazid prophylaxis therapy (IPT) and ART initiation, HIV-1-positive LTBI+ participants (HLTBI+) were followed for up to two years. Before ART initiation, HLTBI+ individuals exhibited the lowest levels of circulating intermediate monocytes, T-cell activation and PD-1 expression, with a decreased frequency of T-regulatory cells and higher circulating IL-10 and IL-17A. PD-1 expression on CD4+ T cell memory subsets, together with opposing anamnestic TNF-α responses to DosR and Rpf, was a discriminatory signature for the HLTBI+ group, as was preserved (following ART) TB-specific TNF-α production, which positively correlated with the CD4/CD8 ratio. Our results highlight an immunomodulatory phenotype conferred by latent TB infection in PLHIV, whose preservation may provide strategies to mitigate TB reactivation.