HIV-1-infection2000HIVTrainedNCT04968717
2000HIV Trained Innate Immunity in HIV Elite Controllers
An observational study of HIV-1-infection, run by Radboud University Medical Center at 3 sites in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- HIV-1-infection
- How many people
- 109 participants
- Where
- 3 sitesNetherlands
- Study dates
- 2 Aug 2021to 27 Oct 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: A recent query of the Dutch national database of HIV (Athena Cohort; Stichting Hiv Monitoring (SHM)) revealed there are approximately 138 HIV elite controllers in the Netherlands, according to the definition used in the 2000HIV study. Of these, 80 HIV elite controllers are expected to participate in the 2000HIV study. Thanks to the query, each one of four 2000HIV participating centers is notified about who the HIV elite controllers in their center are. All HIV elite controllers participating in the 2000HIV will be approached and asked whether they have a first-degree relative who is available and willing to have a single venipuncture.
All participants:
- All participants must be ≥18 years of age.
- Due to distorting effects on immune parameters and immune responses, participation is either not possible or must be delayed in case of the following:
- active hepatitis B/C or signs of acute infections
- active or recent malignant condition (i.e. <12 months ago treated)
- active systemic auto-immune or auto-inflammatory conditions (such as rheumatoid arthritis, inflammatory bowel disease).
- use of immunosuppressive medication
- pregnant
HIV elite controllers:
HIV elite controllers in the 2000HIV that have an available first-degree relative. Definition of HIV elite controller is the same as in the 2000HIV, see definition on page 7 of the protocol and in the group description.
ART-suppressed people living with HIV:
As a control group, ART-suppressed people living with HIV in the 2000HIV that have an available first-degree relative will be included.
ART-suppressed people living with HIV need to apply to the following criteria to participate in the 2000HIV: ≥18 years, on cART ≥6 months with an HIV-RNA load <200 copies/mL.
For this 2000HIV-trained study, additional criteria for ART-suppressed people living with HIV are:
- Never applied to controller definition.
- At least one documented HIV RNA load >100.000 copies/mL
- No documentation of recent HIV acquisition combined with ART initiation in less than 6 months.
Eligible ART-suppressed people living with HIV will be matched by sex and age (max. 5-10 years apart), where possible. Similarity in family members between groups will also be pursued. That is why the HIV elite controllers and their family members will be enrolled first. Thereafter, the ART suppressed people living with HIV and their family members will be recruited and enrolled.
First-degree relatives:
Aside from the criteria for all participants mentioned above, there are no additional criteria for first-degree relatives of participants with HIV. If multiple first-degree relatives are available, siblings are preferred. If no sibling is available, then children >18 years. If no children >18 years, then parents. If there is still multiple options, same-sex will be preferred over different-sex relatives.
Trial locations and contacts
3 sites in 1 country.
Netherlands3 sites
OLVG
Amsterdam
Radboudumc
Nijmegen, 6525GA
Erasmus MC
Rotterdam
About this study
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.
Read the 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:
- (Primary) Investigate if a trained immunity profile in innate immune cells plays a role in HIV elite control.
- (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.
- (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.
- Conditions
- HIV-1-infection
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| HIV elite controllers | Non-viremic elite controller: HIV-positive , > 1 year without cART AND with >3 consecutive HIV-RNA < 75 copies/ml spanning >12 months AND stable CD4> 500 cells/uL.(i.e. >75% of measurements) OR on cART, but before start cART > 1 year without cART AND with >3 consecutive HIV-RNA < 75 copies/ml spanning >12 months AND stable CD4> 500 cells/uL. (i.e. >75% of measurements) Viremic elite controller: HIV-positive >5 year without cART AND with always HIV-RNA >50-10.000 copies/ml AND always CD4> 500 cells/uL. OR on cART, but before start cART >5 year without cART AND with always HIV-RNA >50-10.000 copies/ml AND always CD4> 500 cells/uL | |
| First-degree relatives of HIV elite controllers | Not described | |
| cART-treated non-controller HIV patients | Not described | |
| First-degree relatives of cART-treated non-controller HIV patients | Not described |
What is being measured
The primary outcome is the main question the study is designed to answer.
Direct cytokine responses
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.
Measured: 24 hour ex vivo experiment
Cytokine responses after 6-day training
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.
Measured: 7 day ex vivo experiment
Transcriptome
RNA in the cells will be analysed to gain a transcriptional signature.
Measured: 1 year after sample collection
Epigenome
Epigenetic signatures will be studied by means of ChIP sequencing and ATAC sequencing.
Measured: 1 year after sample collection
Immune phenotyping
Circulating cells are phenotyped by menas of elaborate flow cytometry panels.
Measured: 1 year after sample collection
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jul 2021
- Study start2 Aug 2021
- Primary completion27 Oct 2021
- Study completion27 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIV-1-infectionStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 109 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, Onze Lieve Vrouwe Gasthuis, Elisabeth-TweeSteden Ziekenhuis
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04968717
- Sponsor's protocol ID
- NL76999.091.21
- Other IDs
- 2021-7495
- Acronym
- 2000HIVTrained
- Status last verified
- Nov 2023
- First submitted
- 13 Apr 2021
- Last updated
- 27 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 27 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 2000HIV Trained Innate Immunity in HIV Elite Controllers
- ClinicalTrials.gov ID
- NCT04968717
- Acronym / sponsor ID
- 2000HIVTrained / NL76999.091.21
- Conditions
- HIV-1-infection
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 109 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, Onze Lieve Vrouwe Gasthuis, Elisabeth-TweeSteden Ziekenhuis
- Study start
- 2 Aug 2021 (actual)
- Primary completion
- 27 Oct 2021 (actual)
- Study completion
- 27 Oct 2021 (actual)
- First posted
- 20 Jul 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- (Primary) Investigate if a trained immunity profile in innate immune cells plays a role in HIV elite control.
- (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.
- (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 design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| HIV elite controllers | – | –Non-viremic elite controller: HIV-positive , > 1 year without cART AND with >3 consecutive HIV-RNA < 75 copies/ml spanning >12 months AND stable CD4> 500 cells/uL.(i.e. >75% of measurements) OR on cART, but before start cART > 1 year without cART AND with >3 consecutive HIV-RNA < 75 copies/ml spanning >12 months AND stable CD4> 500 cells/uL. (i.e. >75% of measurements) Viremic elite controller: HIV-positive >5 year without cART AND with always HIV-RNA >50-10.000 copies/ml AND always CD4> 500 cells/uL. OR on cART, but before start cART >5 year without cART AND with always HIV-RNA >50-10.000 copies/ml AND always CD4> 500 cells/uL |
| First-degree relatives of HIV elite controllers | – | – |
| cART-treated non-controller HIV patients | – | – |
| First-degree relatives of cART-treated non-controller HIV patients | – | – |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- A recent query of the Dutch national database of HIV (Athena Cohort; Stichting Hiv Monitoring (SHM)) revealed there are approximately 138 HIV elite controllers in the Netherlands, according to the definition used in the 2000HIV study. Of these, 80 HIV elite controllers are expected to participate in the 2000HIV study. Thanks to the query, each one of four 2000HIV participating centers is notified about who the HIV elite controllers in their center are. All HIV elite controllers participating in the 2000HIV will be approached and asked whether they have a first-degree relative who is available and willing to have a single venipuncture.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Direct cytokine responses
Time frame: 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
Time frame: 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
Time frame: 1 year after sample collection
RNA in the cells will be analysed to gain a transcriptional signature.
Epigenome
Time frame: 1 year after sample collection
Epigenetic signatures will be studied by means of ChIP sequencing and ATAC sequencing.
Immune phenotyping
Time frame: 1 year after sample collection
Circulating cells are phenotyped by menas of elaborate flow cytometry panels.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Nov 2023.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV-1-infection, run by Radboud University Medical Center at 3 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Direct cytokine responses (time frame: 24 hour ex vivo experiment). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Nov 2023; AzTrials last refreshed its copy on 6 Nov 2026.