2000HIV Trained Innate Immunity in HIV Elite Controllers

Completed

• Conditions: HIV-1-infection

• Registration Number: NCT04968717
• Lead Sponsor: Radboud University Medical Center

Brief Summary

Some individuals are able to spontaneously control HIV replication, the so-called 'elite controllers' (ECs). ECs are crucial for our understanding of HIV infection. While there is more and more evidence pointing towards a role of the innate immune system in elite control, no research has been performed on the role of innate trained immunity in elite control of HIV.

In this cross-sectional case-control study, we will study this role of trained immunity in HIV elite control by comparing ECs both to a non-HIV-infected first-degree relative, and to HIV patients who are not elite controllers. In addition, we will study whether HIV itself can induce a trained innate immunity phenotype.

Detailed Description

Rationale:

It remains unknown how some individuals spontaneously control HIV in the absence of antiretroviral medication, called HIV 'elite controllers' (ECs). ECs have been absolutely crucial to our current understanding of control of HIV replication. While research has mainly focused on the adaptive immune system, there is a vast amount of evidence indicating that the innate immune system is essential to HIV elite control.

Trained innate immunity can be expressed in terms of enhanced responsiveness of innate immune cells to a repeated trigger. This occurs through epigenetic remodeling after exposure to certain stimuli, such as beta-glucan, lipopolysaccharide (LPS) or the bacillus Calmette-Guérin (BCG) vaccine. Innate training results in an altered gene expression and metabolic reqiring on a cellular level, resulting in greater resistance against subsequent infection.

Both the impact of trained immunity on HIV infections and vice versa, the impact of HIV on trained immunity, are unknown. Our hypothesis is that ECs are natural hyper-responders to innate immune training triggers and that this aids in the HIV elite control phenotype.

Objectives:

1. (Primary) Investigate if a trained immunity profile in innate immune cells plays a role in HIV elite control.

2. (Secondary) Determine the immune phenotypes that distinguish family members of HIV elite controllers from family members of people living with HIV who have never been controllers.

3. (Secondary) Determine whether HIV can induce a long-term functional and transcriptional program in innate immune cells similar to trained immunity.

Study design:

Cross-sectional case-control study.

For the primary objective, HIV elite controllers will be compared to ART-suppressed HIV patients who never have been elite controllers and first-degree relatives of HIV elite controllers will be compared to first-degree relatives of ART-suppressed HIV patients who have never been elite controllers.

For the secondary objectives, first, a system biology approach will be used in the comparison above. To determine the role of HIV in trained innate immunity we will compare people living with HIV (both controllers as non-controllers) to their respective family members.

Study Timeline

• Study First Submitted: 2021-04-13
• Study First Submitted QC: 2021-07-08
• Study First Posted: 2021-07-20
• Study Start: 2021-08-02
• Primary Completion: 2021-10-27
• Study Completion: 2021-10-27
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-23
• Last Update Posted: 2023-11-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 109

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Direct cytokine responses	24 hour ex vivo experiment	Isolated monocytes and NK-cells will be stimulated ex vivo with a range of stimuli. Cytokines released in the supernatants will be measured by ELISA.
Cytokine responses after 6-day training	7 day ex vivo experiment	Isolated monocytes and NK-cells will be trained ex vivo and the innate training effect will be studied after restimulation with an unrelated stimulus on day 7. Cytokines released in the supernatant and intracellularly will be measured by ELISA.
Transcriptome	1 year after sample collection	RNA in the cells will be analysed to gain a transcriptional signature.
Epigenome	1 year after sample collection	Epigenetic signatures will be studied by means of ChIP sequencing and ATAC sequencing.
Immune phenotyping	1 year after sample collection	Circulating cells are phenotyped by menas of elaborate flow cytometry panels.

Trial Locations

Locations (3)

OLVG; 🇳🇱 Amsterdam, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Radboudumc; 🇳🇱 Nijmegen, Netherlands