Interaction Between HIV and Platelets (PLAQUEVIH)

March 15, 2023 updated by: Assistance Publique - Hôpitaux de Paris

Interaction of HIV/Platelets and HIV-platelets/Lymphocytes in HIV Patients Under cART Treatment But Immunological Non Responders

The investigators propose that the lack of immune response in InR is driven by HIV-containing platelets that might interact with macrophages and CD4+ T-cells although by different mechanisms. In the one hand, HIV-sheltering platelets might fuel tissue HIV macrophage and in turn T cell reservoirs as observed in InRs and/or maintain a low-level viral replication in macrophages, sustaining a persistent inflammatory profile on in these cells. In the other hand,HIV-sheltering platelets might induce CD4+ T-cells dysfunctions via platelets/ectosomes, although without promoting platelet-to-T-cell HIV transfer/infection, thereby increasing the number of peripheral inflammatory TH17 cells and a TH17/Treg unbalance as observed in InRs.

Main Objectives:

i) To characterize and the molecular and functional level the platelet factors implicated in HIV transfer to tissue-like macrophages as well as in the immunomodulatory activity of HIV-containing platelets on macrophages and CD4+ T-cells.

ii) To interrogate the transfer of HIV-containing platelet-derived mRNA and microRNA to tissue-like macrophages and CD4+ T-cells as one major mechanism of target cell immunomodulation.

iii) To investigate the therapeutic potential of anti-platelet aggregation/activation agents (e.g. Abciximab), known to block platelet-immune cell interaction, in improving immune cell functions in vitro and promoting immunological recovery in vivo.

Study Overview

Status

Recruiting

Conditions

Detailed Description

The investigators have recently shown that infectious HIV is carried by platelets in the blood of HIV-infected patients which failed to respond immunologically to cART despite viral suppression (Immunological nonresponders, InRs) and that platelets can mediate HIV transmission to macrophages in vitro, in line with our recent description of HIV reservoir occurrence and establishment in macrophages in cART-suppressed patients. Around 20% of the overall cART-treated patients are InRs that fail to reconstitute their competent immune status despite treatment observance with prolonged viral suppression. The causes of this immunological failure remain unclear and no treatment is available to improve the health of InRs, which are at higher risk of AIDS and non-AIDS morbidity and mortality. The poor immunological recovery in InRs is mainly driven by a sustained low CD4+ T-cell counts that relies on persistent inflammation and immune activation affecting T-cell population profile.

Platelets are cleared by tissue macrophages in vivo in physiological or inflammatory contexts, what could represent a route for HIV to establish reservoirs in macrophages. We have shown that HIV sheltered in platelets can transfer infection to macrophages, in a process blocked by anti-αIIb/ β3 antibody Abciximab. This infection is productive as in turn, infection spreads replication-competent virus to non-infected CD4+ T-cells. This viral spread may increase the blood T-cell HIV reservoir, a hallmark of immunological failure as observed in InRs. In contrast, HIV-containing platelets fail to directly infect CD4+ T, unless infection is forced by the fusion inducer polybrene. Thus, in contrast to macrophages, CD4+ T cells are not targeted by HIV enclosed in platelets.

However, HIV-containing platelets might immunomodulate CD4+ T cell functions thereby triggering the immunological failure observed in cART-suppressed patients. Hence, platelet-T-cell conjugates form in the blood of HIV patients, suggesting that HIV-containing platelets could downregulate T-cell functions. Platelets are known to express adhesive proteins that not only promote platelet aggregation responsible for primary hemostasis, but also to mediate interactions with leukocytes, driving either inhibition of proliferation and differentiation of CD4+ T-cells into TH17, crucial in mediating chronic inflammation. Platelets can also shed microvesicles (ectosomes) which directly contact these lymphocytes, driving TH17 polarization of CD4+ T-cells and in turn an unbalanced TReg/TH17 ratio characteristic of InRs. Such TReg/TH17 unbalance might reflect a persistent inflammatory state that could translate in a cytotoxic/antiproliferative effect on CD4+ T-cells and ultimately immunological failure.

Very recently, we found that the number of platelets-CD4+ T-cells conjugates circulating in the blood of cART-treated HIV-infected patients is increased in InRs (virally suppressed and <350 CD4+T-cells/μl) compared with immunological responders (IR, >500 CD4+T-cells/μl). In addition, conjugates form more with TH17 in InR compared with IR, whereas conjugates form equally with TReg in the two InR and IR patients groups. These results indicate that InRs not only present a strong probability to have HIV-containing platelets but are also prone to form platelets-TH17 cells conjugates, suggesting a causal connection between association of HIV with platelets and platelet-driven immunomodulation of CD4+T-cells toward a TH17 profile. Whether these platelet-TH17 conjugates we observed form with full platelets or platelet ectosome (that both harbor CD41 used as platelet marker in our conjugate analyses) remains unknown.

Importantly, HIV RNA is only detected in circulating CD4+ T-cell reservoirs when latent proviral DNA is reactivated, suggesting that platelet-containing HIV does not conjugate with CD4+T cell in InR patients but rather with bystander platelets or platelet ectosomes (lacking HIV). Thus, immunomodulation of CD4+T cells in InRs might result from the interaction with these bystander platelet/ectosomes or ectosomes shed from HIV-containing platelets.

Platelets have been shown to exchange mRNA upon interaction with immune cells and tumors . Furthermore, transfer of functional mRNA and microRNA is so far demonstrated to be mediated by platelet ectosomes, targeting macrophage/monocytic and epithelial cells. Thus, transfer of messenger RNAs or microRNAs from platelets/ectosomes to macrophages and/or CD4+ T-cells could be the mechanism of platelet-dependent immunomodulation of target leukocytes. Platelets display a repertoire of mainly pro-inflammatory microRNAs such as miRNA-155 and miRNA-326, involved in NF-κB-mediated inflammatory macrophage responses 25 and TH17 cell-polarization. These miRNAs could be differentially expressed in platelets containing HIV and their eventual transfer to target immune cells could participate in immune cell dysfunction as observed in InRs. Furthermore, αIIb/ β3 mRNA are platelet-specific transcripts conserved in circulating platelets throughout their life-span, and can be exploited to tag leukocytes targeted by mRNA/microRNA of HIV-containing platelets.

Study Type

Observational

Enrollment (Anticipated)

240

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Boulogne Billancourt, France, 92100
        • Recruiting
        • Service Hématologie Immunologie, Hôpital Ambroise Paré

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

200 VIH positive patients without lymphome + 20 VIH positive patients with lymphome + 20 healthy volunteers (VIH negative).

Description

Inclusion Criteria:

For all patients:

  • aged ⩾ 18 years;
  • patients who can read and understand information document.

For VIH positive patients without lymphoma:

  • VIH positive patients with negative or positive viral load under cART since 1 year;
  • patient under cART.

For VIH positive patients with lymphoma:

  • VIH positive patient with negative viral load under cART since 1 year;
  • patient with lymphoma.

For Healthy Volunteers:

  • VIH negative patient (control) already included in clinical trial;
  • patient major without haematological pathology.

Exclusion Criteria:

  • patient < 18 years;
  • Unable to read and understand information document.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
VIH positive patients without lymphoma
200 VIH positive patients without lymphoma
VIH positive patients with lymphoma
20 VIH positive patients with lymphoma
healthy volunteers
20 healthy volunteers

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CD4 number will be determined
Time Frame: at 48 month
Immunological response status based on the presence-absence of HIV in platelets during follow-up: CD4 number will be determined by flow cytometry.
at 48 month
VIH level in platelet will be quantified
Time Frame: at 48 month
Immunological response status based on the presence-absence of HIV in platelets during follow-up: VIH level in platelet will be quantified by flow fich and PCR.
at 48 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
potential interaction between platelets and lymphocytes
Time Frame: 12-36 months
in vitro characterization of interaction between lymphocytes and platelets by microscopy. The cells will be stained with specific antibodies
12-36 months
potential interaction between platelets and lymphocytes
Time Frame: 12-36 months
in vitro characterization of interaction between lymphocytes and platelets by flow cytometry. The cells will be stained with specific antibodies
12-36 months
analyze if the interaction can be blocked by anti GPIIbIIIa
Time Frame: 12-36 months
anti GPIIbIIIa will be added in culture dish with platelets and lymphocytes. Analysis of inhibition of interaction will be performed by flow cytometry.
12-36 months
analyze if the interaction can be blocked by anti GPIIbIIIa
Time Frame: 12-36 months
anti GPIIbIIIa will be added in culture dish with platelets and lymphocytes. Analysis of inhibition of interaction will be performed by microscopy.
12-36 months
HIV expression on bone marrow smear
Time Frame: 1-48 months
cells from bone marrow will be spread on a slide; and presence of HIV will be performed with an anti HIV anti body
1-48 months
soluble factors secretion
Time Frame: 12-36 months
HIV+ platelets will be cultivated with donor's CD4 lymphocytes of. By ELISA and/or Bioplex, the secretion of soluble factors (cytokines, chemokines, soluble receptors), secreted by Lymphocytes in the culture medium will be studied.
12-36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France

Investigators

  • Principal Investigator: Claude Capron, MD, Service Hématologie Immunologie, Hôpital Ambroise Paré
  • Study Director: MORGANE BOMSEL, MD, Unité CNRS UMR 8104, INSERM U1016, Laboratoire Entrée muqueuse du VIH et Immunité muqueuse, Département Infection, Immunité et Inflammation, Institut Cochin Université Paris Descartes

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 17, 2020

Primary Completion (Anticipated)

March 1, 2025

Study Completion (Anticipated)

March 1, 2025

Study Registration Dates

First Submitted

July 1, 2019

First Submitted That Met QC Criteria

August 19, 2019

First Posted (Actual)

August 20, 2019

Study Record Updates

Last Update Posted (Actual)

March 17, 2023

Last Update Submitted That Met QC Criteria

March 15, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19CCN-VIH-Plaquettes

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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