Ex Vivo Characterization and Targeting of the Latent HIV Infected Reservoir to Cure HIV (EX VIVO)

Combination antiretroviral therapy (cART) blocks intracellular human immunodeficiency virus (HIV) replication in CD4+ T-lymphocytes, but fails to eliminate latent HIV infected CD4+ T-lymphocytes. About 7 (range <1-100) in 106 of these cells are latently infected and can cause reactivation of proviral HIV when cART is stopped. These latently infected cells form the reservoir and must be targeted in order to cure HIV. We would like to further investigate this reservoir and assess potential interventions to eradicate it. One promising option is to further study the influence of HIV latency disruptors (latency reversing agents, LRA) on the HIV infected reservoir. These agents are used in shock and kill strategies that disrupt latency by LRA followed by the selective (induced) killing of the reservoir cell due to viro-pathogenic effects.

For accurate assessment of the reservoir and potential cure strategies, including the impact of LRA on the reservoir, a large reservoir and sufficient cells for analysis are desirable. Our understanding on the reservoir comes from in vitro lymphocyte models and early ex vivo studies. Additional studies of patients with different clinical phenotypes including untreated versus treated versus the rare individuals that control HIV spontaneously are increasingly relevant to the field. Especially this last category represent biological examples of viral control without cART and are useful to study the factors that set them apart from those that need treatment for their HIV. This study aims to deepen our understanding of the HIV reservoir and cure strategies, foremost, shock and kill strategies. We will do this by setting up a durable ex vivo platform for HIV reservoir and cure studies of which the samples can be used for hypothesis generation for in-vivo studies.

A project from the Erasmus MC HIV Eradication Group (EHEG).

Study Overview

• Status: Recruiting
• Conditions: HIV Infections; HIV-1-infection; HIV-2 Infection

Detailed Description

This is a prospective cross-sectional cohort study used for ex vivo studies using material from HIV infected individuals. Peripheral blood mononuclear cells (PBMC's) and whole blood are obtained through leukapheresis and blood sampling at a single timepoint. Relevant clinical data will be collected to support interpretation of ex vivo experimental results. In vitro experiments are performed on patient derived material. In a substudy, patients can consent to longitudinal follow up with yearly sampling for 4 years.

Reservoir characteristics and efficacy of shock and kill strategies as defined in the endpoints will be explored between patients with different HIV clinical phenotypes. This allows us to identify discriminative factors useful to develop future cure strategies in clinic. We will therefore aim to include the following patients groups in the cohort:

• HIV-1 patients including B and non-B subtypes patients
• HIV-2 patients
• Long term non progressors (plasma HIV-RNA <2000c/mL without cART)
• Elite controllers (plasma HIV-RNA <50c/mL without cART)
• Post-treatment controller (plasma HIV-RNA <2000c/mL after permanent cART interruption)

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Casper Rokx, MD PhD; Email: c.rokx@erasmusmc.nl
• Study Contact Backup: Name: Rob Gruters, PhD; Email: r.gruters@erasmusmc.nl

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Centre
    • Contact: Rokx Casper, MD PhD
    • Principal Investigator: Casper Rokx, MD PhD
    • Principal Investigator: Tokameh Mahmoudi, PhD
    • Principal Investigator: Rob Gruters, PhD
    • Principal Investigator: Peter Katsikis, Prof
    • Sub-Investigator: Shringar Rao, PhD
    • Sub-Investigator: Raquel Crespo Galvan, MSc
    • Sub-Investigator: Shahla Romal
    • Sub-Investigator: Tonmoy Hossain, MSc
    • Sub-Investigator: Henrieke Prins, MD
    • Sub-Investigator: Albert Groenendijk, MD
    • Sub-Investigator: Kathryn Hensley, MD
    • Sub-Investigator: Cynthia Lungu, MSc
    • Sub-Investigator: Peter te Boekhorst, MD PhD
    • Sub-Investigator: Yvonne Muller, PhD
    • Sub-Investigator: Els van Nood, MD PhD
    • Sub-Investigator: Mariana Mendonca melo, MD
    • Sub-Investigator: Annelies Verbon, Prof
    • Sub-Investigator: Jeroen van Kampen, MD PhD
    • Sub-Investigator: David vd Vijver, PharmD PhD
    • Sub-Investigator: Birgit Koch, Prof
    • Sub-Investigator: Thibault Mespede, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Otherwise healthy adult HIV infected patients will be recruited at the Erasmus MC outpatient clinic of infectious diseases

Description

Inclusion Criteria:

1. Age 18 years or older.
2. Confirmed HIV-1 or HIV-2 infection.

Exclusion Criteria:

1. Inability to place 2.5 cm venous catheter or perform phlebotomy

2. Major comorbidities:

   A. Severe symptomatic anemia B. Recent symptomatic cardiovascular event (unstable angina pectoris, decompensated heart failure, myocardial infarction).

3. The inability to participate due to any other relevant medical, social, environmental, psychological, factors or according to the HIV treating physician's judgement

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The number of HIV patients with a measurable proviral reservoir measured by molecular, flowcytometric and culture based assays	10-15 years

Secondary Outcome Measures

Outcome Measure	Time Frame
The level of reactivation of latently HIV infected PBMCs after treatment ex vivo with established and novel HIV cure compounds (alone and in combination) as assessed by cell-associated HIVRNA.	10-15 years
To measure predictive biomarkers of the size and activity of the latent HIV reservoir as assessed by molecular, flowcytometric and culture based assay ex vivo.	10-15 years
The number of newly setup assays that measure the size of the proviral reservoir and are validated with current established molecular, flowcytometric and culture based assays.	10-15 years
The HIV reservoir size and activity as assessed by molecular, flowcytometric, and culture based assays ex vivo.	10-15 years
The HIV reservoir susceptibility to shock and kill strategies as assessed by molecular, flowcytometric, and culture based assays.	10-15 years
The HIV reservoir size, activity, and susceptibility to shock and kill strategies in relation to clinical phenotypes.	10-15 years

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Principal Investigator: Casper Rokx, MD PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2012
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: December 15, 2021
• First Submitted That Met QC Criteria: January 17, 2022
• First Posted (Actual): January 31, 2022

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: HIV; HIV cure; HIV reservoir
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases
• Other Study ID Numbers: NL42819.078.12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No