Ignite Creation Date:
2024-05-06 @ 1:35 PM
Last Modification Date:
2024-10-26 @ 1:16 PM
Study NCT ID:
NCT04062825
Status:
RECRUITING
Last Update Posted:
2023-03-17
First Post:
2019-07-01
Brief Title:
Interaction Between HIV and Platelets
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Interaction of HIVPlatelets and HIV-plateletsLymphocytes in HIV Patients Under cART Treatment But Immunological Non Responders
Status:
RECRUITING
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PLAQUEVIH
Brief Summary:
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 andor maintain a low-level viral replication in macrophages sustaining a persistent inflammatory profile on in these cells In the other handHIV-sheltering platelets might induce CD4 T-cells dysfunctions via plateletsectosomes although without promoting platelet-to-T-cell HIV transferinfection thereby increasing the number of peripheral inflammatory TH17 cells and a TH17Treg 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 aggregationactivation agents eg Abciximab known to block platelet-immune cell interaction in improving immune cell functions in vitro and promoting immunological recovery in vivo
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 aggregationactivation agents eg Abciximab known to block platelet-immune cell interaction in improving immune cell functions in vitro and promoting immunological recovery in vivo
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 TRegTH17 ratio characteristic of InRs Such TRegTH17 unbalance might reflect a persistent inflammatory state that could translate in a cytotoxicantiproliferative 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 CD4T-cellsμl compared with immunological responders IR 500 CD4T-cellsμl 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 CD4T-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 CD4T cell in InR patients but rather with bystander platelets or platelet ectosomes lacking HIV Thus immunomodulation of CD4T cells in InRs might result from the interaction with these bystander plateletectosomes 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 macrophagemonocytic and epithelial cells Thus transfer of messenger RNAs or microRNAs from plateletsectosomes to macrophages andor 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 mRNAmicroRNA of HIV-containing platelets
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 TRegTH17 ratio characteristic of InRs Such TRegTH17 unbalance might reflect a persistent inflammatory state that could translate in a cytotoxicantiproliferative 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 CD4T-cellsμl compared with immunological responders IR 500 CD4T-cellsμl 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 CD4T-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 CD4T cell in InR patients but rather with bystander platelets or platelet ectosomes lacking HIV Thus immunomodulation of CD4T cells in InRs might result from the interaction with these bystander plateletectosomes 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 macrophagemonocytic and epithelial cells Thus transfer of messenger RNAs or microRNAs from plateletsectosomes to macrophages andor 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 mRNAmicroRNA of HIV-containing platelets
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None