Chronic HIV infection leads to a dysregulated immune system, even if viral suppression is achieved by combination AntiRetroviral Therapy (ART). On the one hand, HIV causes persistent immune activation, which is related to an array of common non-AIDS related diseases such as cardiovascular disease (CVD), Non-Alcoholic Fatty Liver Disease (NAFLD), non-AIDS defining malignancies and neuropsychiatric disorders.  On the other hand, accelerated aging/depletion (senescence) of the immune system hinders effective immunity against infectious diseases and cancer.

Likewise, this derailed inflammatory balance creates a niche for persisting viral replication and reservoir and prevents cure or functional cure. Mechanisms behind these phenomena are poorly understood. Restoring this balance has proven to be challenging and new targets for effectively restoring it are lacking. An integrative view on the functionality of different traits of the immune system is therefore warranted.

Studies within the Human Functional Genomics Project (HFGP) have shown such integrative view in healthy subjects and certain disease cohorts. A pilot HFGP study including 200 people living with HIV using ART also provided the first insights in immune dysregulation in these patients. Inclusion of a 10 times larger cohort of 2000 people living with HIV using ART , also with more extreme clinical phenotypes allows a more precise assessment of the factors underlying the immune dysregulation. Participants will be allocated to a discovery cohort (n=1200) and a validation cohort (n=800). The immune function will be extensively evaluated and multiple omics data will be analyzed, allowing the identification of pathways and biomarkers that may eventually result in new, targeted treatments, restoring the balance in immunity and inflammation, reducing HIV-related morbidity and mortality, and pave the way for effective strategies on viral elimination.

The following information and materials will be available:

Baseline analyses

  • General questionnaires on lifestyle, diet, well-being
  • Psychiatric questionnaires
  • Clinical data:
    • Medical history
    • Liver and cardiovascular risk factors
  • Whole blood differentiation cell count
  • DNA for genomic and epigenomic analysis
  • PBMCs for ChIPseq, ATACseq, and transcriptome analysis
  • Microbiome samples: intestinal, salivary
  • Serum and plasma for metabolomic and targeted proteomic analyses
  • Immune cell subpopulations and immunoglobin subclasses determined by flow cytometry
  • Functional immunology: cellular immunity using ex vivo PBMC stimulation
  • Freshly frozen PBMCs
  • Urine
  • HIV reservoir measurements
  • Assessment of liver fibrosis/steatosis by ultrasound and FibroScan
  • Assessment of subclinical CVD by intima media thickness measurements and plaque detection of carotid artery by ultrasound as well as analysis ECG abnormalities

2-Year follow-up analyses

  • General questionnaires on lifestyle, diet and well-being
  • Psychiatric questionnaires
  • Clinical data:
    • Medical history
    • Liver and cardiovascular risk factors (in a subset of patients)
  • Whole blood differentiation cell count
  • Serum and plasma for follow-up biomarker analysis
  • Assessment of liver fibrosis/steatosis by ultrasound and FibroScan

Further details can also be seen at ClinicalTrials.gov: NCT03994835

Ethical approval:
The 2000HIV study has been reviewed and approved by the Medical Research Ethics Committee Region Arnhem-Nijmegen under the reference number NL68056.091.81.

Funding:
The 2000HIV Human Functional Genomics Partnership Program (2000HIV Study) is supported by ViiV Healthcare.