Circulating microparticles are increased amongst people presenting with HIV and advanced immune suppression in Malawi and correlate closely with arterial stiffness: a nested case control study

Background: We aimed to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with human immunodeficiency virus (HIV) and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Antiretroviral therapy (ART)-naïve adults with a new HIV diagnosis and CD4 <100 cells/µL had microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic blood pressure (BP) and diastolic BP in a 1:1 ratio.  Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. Results: The median (IQ) total CMP count for 71 participants was 1 log higher in HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.47, p<0.001). In adjusted analysis, every log increase in circulating particles showed a 20% increase in cfPWV (95% confidence interval [CI] 4 – 40%, p=0.02). In terms of subsets, endothelial and platelet derived microparticles were most strongly associated with HIV. Endothelial derived E-selectin+ CMPs were 1.3log-fold higher and platelet derived CD42a+ CMPs were 1.4log-fold higher (both p<0.0001). Endothelial and platelet derived CMPs also correlated most closely with arterial stiffness (spearman rho: E-selectin+ 0.57 and CD42a 0.56, both p<0.0001). Conclusions: Circulating microparticles associate strongly with arterial stiffness among people living with HIV in Malawi. Endothelial damage and platelet microparticles are the predominant cell origin types and future translational studies could consider prioritising these pathways

HIV-related arterial stiffness in Malawian adults is associated with proportion of PD-1 expressing CD8 T-cells and reverses with anti-retroviral therapy

Background The contribution of immune activation to arterial stiffness and its reversibility in HIV-infected adults in sub-Saharan Africa is unknown. Methods HIV-uninfected and HIV-infected Malawian adults initiating antiretroviral therapy (ART) with CD4 &lt;100 cells/l were enrolled (2-weeks post-ART for HIV-infected) and followed for 44-weeks. We evaluated the relationship between carotid femoral pulse wave velocity (cfPWV) and T-cell activation (HLADR+CD38+), exhaustion (PD1+) and senescence (CD57+), and monocyte subsets using normal regression. Results In 279 HIV-infected and 110 HIV-uninfected adults, 142(37%) had hypertension. HIV was independently associated with 12% higher cfPWV (p=0.02) at baseline, and week-10 (14% higher, p=0.02) but resolved by week-22. CD4 and CD8 T-cell exhaustion(PD1+) were independently associated with higher cfPWV at baseline (p=0.02). At 44-weeks, arterial stiffness improved more in those with greater decreases in %CD8 and %CD8PD1+ T-cells (p=0.01, p=0.03 respectively). When considering HIV-infected participants alone, adjusted arterial stiffness at week-44 tended to be lower in those with higher baseline %CD8PD1+ T-cells (p=0.054). Conclusions PD-1+ expressing CD8 T-cells are associated with HIV-related arterial stiffness, which remains elevated during the first three months on ART. Resources to prevent cardiovascular disease in sub-Saharan Africa should focus on blood pressure reduction, and those with low CD4 during early ART

HIV-related arterial stiffness in Malawian adults is associated with proportion of PD-1 expressing CD8 T-cells and reverses with anti-retroviral therapy

Arterial stiffness is increased in Malawian adults with low CD4 during the first 3 months of antiretroviral therapy, compared to adults without HIV. Hypertension is an important traditional risk factor and immune activation, including CD8 exhaustion, also contributes to arterial stiffness

Inflammatory phenotypes predict changes in arterial stiffness following ART initiation

Background Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesised that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. Methods We recruited Malawian adults with CD4<100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse wave velocity (cfPWV) measured arterial stiffness 2, 12, 24 and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. Results 211 HIV-positive participants grouped into three clusters of inflammatory marker profiles representing 51 (24%) (cluster-1), 153 (73%) (cluster-2) and 7 (3%) (cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD1 vs cluster-2 and cluster-3 (all p<0.0001). Although small, individuals in cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL6, IFNɣ, IP10, IL1RA, IL10), chemotaxis (IL8), systemic and vascular inflammation (CRP, ICAM1, VCAM1) and SAA (all p<0.001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 vs cluster-1 (relative-fold-change 0.99 (95% CI 0.86-1.14, p=0.91, but greater in cluster-3 vs cluster-1 (relative-fold-change 1.45 (95% CI 1.01-2.09, p=0.045). Conclusions Two inflammatory clusters were identified: one defined by high T-cell PD1 expression and another by a hyper-inflamed profile and increases in cfPWV on ART. Further clinical characterisation of these inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk