Increased Platelet-CD4+ T Cell Aggregates Are Correlated With HIV-1 Permissiveness and CD4+ T Cell Loss

Abstract

Chronic HIV-1 infection is associated with persistent inflammation, which contributes to disease progression. Platelet-T cell aggregates play a critical role in maintaining inflammation. However, the phenotypic characteristics and clinical significance of platelet-CD4+ T cell aggregates remain unclear in different HIV-infected populations. In this study, we quantified and characterized platelet-CD4+ T cell aggregates in the peripheral blood of treatment-naïve HIV-1-infected individuals (TNs), immunological responders to antiretroviral therapy (IRs), immunological non-responders to antiretroviral therapy (INRs), and healthy controls (HCs). Flow cytometry analysis and immunofluorescence microscopy showed increased platelet-CD4+ T cell aggregate formation in TNs compared to HCs during HIV-1 infection. However, the frequencies of platelet-CD4+ T cell aggregates decreased in IRs compared to TNs, but not in INRs, which have shown severe immunological dysfunction. Platelet-CD4+ T cell aggregate frequencies were positively correlated with HIV-1 viral load but negatively correlated with CD4+ T cell counts and CD4/CD8 ratios. Furthermore, we observed a higher expression of CD45RO, HIV co-receptors, HIV activation/exhaustion markers in platelet-CD4+ T cell aggregates, which was associated with HIV-1 permissiveness. High levels of caspase-1 and caspase-3, and low levels of Bcl-2 in platelet-CD4+ T cell aggregates imply the potential role in CD4+ T cell loss during HIV-1 infection. Furthermore, platelet-CD4+ T cell aggregates contained more HIV-1 gag viral protein and HIV-1 DNA than their platelet-free CD4+ T cell counterparts. The platelet-CD4+ T cell aggregate levels were positively correlated with plasma sCD163 and sCD14 levels. Our findings demonstrate that platelet-CD4+ T cell aggregate formation has typical characteristics of HIV-1 permissiveness and is related to immune activation during HIV-1 infection.

Alterations in circulating markers in HIV/AIDS patients with poor immune reconstitution: Novel insights from microbial translocation and innate immunity

“…A multicenter cohort study reported that levels of inflammatory and immune activation biomarkers, including sCD163, declined following ART initiation (71). Some studies have also reported no elevated sCD163 levels in PLWH after ART (72, 73 (68). Additionally, the percentage of platelet-CD4+ T cell aggregates was positively linked with the expression of sCD14 and sCD163, which were connected to an enhanced risk of cardiovascular disease (CVD) and can function as indicators of the evolution of HIV illness (75-77).…”

“…Xiaopeng Dai et al. found that plasma sCD163 levels were shown to be higher in INRs compared with UCs, and that ART boosted sCD163 levels in IRs ( 68 ). Additionally, the percentage of platelet-CD4+ T cell aggregates was positively linked with the expression of sCD14 and sCD163, which were connected to an enhanced risk of cardiovascular disease (CVD) and can function as indicators of the evolution of HIV illness ( 75 – 77 ).…”

Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era

“…In HIV infection, it has been described that activated platelets binding to CD8 + and CD4 + T cells prevent proper activation and control long-term immune dysfunction. 67 However, whether these mechanisms are mediated by eATP or chronic purinergic receptor activation is not well described. Our data indicate that healthy eATP and HAD-associated eATP levels did not change the expression and distribution of key adhesion and junctional molecules, suggesting an adaptation.…”

Platelet, a key regulator of innate and adaptive immunity

“…Activated platelet-derived IL-33, Dkk-1, and 5-HT or CD40L induce type 2 immune response or interact with TSLP-stimulated myeloid DCs to tune the sensitization stage of allergic asthma through RANK/ RANKL signaling (128). In addition, platelet-CD4 + T-cell aggregate frequency was positively correlated with HIV-1 viral load and was related to immune activation during HIV-1 infection (129). HIV-containing platelets result in dysfunction of glycolysis-mediated energy production in CD4 + T cells.…”