Biomarkers of Endothelial Activation in Black South African HIV-Positive Subjects are Associated with Both High Viral Load and Low CD4 Counts

Mezoh, Genevieve; Lutchman, Nereshni; Worsley, Catherine M.; Gededzha, Maemu P.; Mayne, Elizabeth; Martinson, Neil; Moore, Penny L.; Crowther, Nigel J

doi:10.1089/aid.2021.0052

Cited by 6 publications

(6 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our immunological findings are consistent with those from outpatient studies from SSA, in which ART-naïve PWH exhibit exaggerated pro-inflammatory innate immune activation, T-cell activation and exhaustion, endotheliopathy, and coagulopathy [33–37]. This immune dysregulation, likely multifactorial and due to opportunistic co-infections, microbial translocation, and viral replication, is only partly mitigated by suppressive ART, suggesting residual HIV-driven immune activation [36–39].…”

Section: Discussionsupporting

confidence: 87%

HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda

Cummings

Bakamutumaho²,

Price

et al. 2022

Aids

View full text Add to dashboard Cite

Background:The global burden of sepsis is concentrated in high HIV-burden settings in sub-Saharan Africa (SSA). Despite this, little is known about the immunopathology of sepsis in persons with HIV (PWH) in the region. We sought to determine the influence of HIV on host immune responses and organ dysfunction among adults hospitalized with suspected sepsis in Uganda.Design: Prospective cohort study. Methods:We compared organ dysfunction and 30-day outcome profiles of PWH and those without HIV. We quantified 14 soluble immune mediators, reflective of key domains of sepsis immunopathology, and performed whole-blood RNA-sequencing on samples from a subset of patients. We used propensity score methods to match PWH and those without HIV by demographics, illness duration, and clinical severity, and compared immune mediator concentrations and gene expression profiles across propensity score-matched groups.Results: Among 299 patients, 157 (52.5%) were PWH (clinical stage 3 or 4 in 80.3%, 67.7% with known HIV on antiretroviral therapy). PWH presented with more severe physiologic derangement and shock, and had higher 30-day mortality (34.5% vs. 10.2%; P < 0.001). Across propensity score-matched groups, PWH exhibited greater pro-inflammatory immune activation, including upregulation of interleukin (IL)-6, IL-8, IL-15, IL-17 and HMGB1 signaling, with concomitant T-cell exhaustion, prothrombotic pathway activation, and angiopoeitin-2-related endothelial dysfunction.

show abstract

Section: Discussionsupporting

confidence: 87%

HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda

Cummings

Bakamutumaho²,

Price

et al. 2022

Aids

View full text Add to dashboard Cite

show abstract

“…Eighty (80) PLWH, ART-naïve Black South African individuals between the ages of 30 to 50 years were recruited from the Nthabiseng and Zazi Clinics, Chris Hani Baragwanath Hospital, as described in our previous study (Mezoh et al, 2021). Subjects with clinical conditions known to influence endothelial function, as defined in Mezoh et al, 2021, were excluded from this study. Subjects were screened for HIV at a walk-in point of care HIV testing service, using the Bioline HIV 1/2 3.0 rapid test kit (Standard Diagnostics Inc, Gyeonggi-do, Republic of Korea) (Govender et al, 2014) and HIV seropositivity was confirmed using the Cobas® HIV-1 quantitative nucleic acid test on the Cobas® automated 6800 system.…”

Section: Methodsmentioning

confidence: 99%

Section: Hiv-1 Clinical Isolatesmentioning

confidence: 99%

“…Chronic activation of the endothelium results in a dysfunctional state, which can lead to vascular damage, including the progression of atherosclerosis (Deanfield et al, 2007). Studies conducted on PLWH show that endothelial activation, as assessed using plasma biomarkers such as VCAM-1 and ICAM-1, demonstrate a broad concentration of these proteins that overlap with those in HIV-unaffected subjects (Graham et al, 2013, Fourie et al, 2015, Mezoh et al, 2021). This differential effect of the virus on endothelial activation may arise from either the genetic heterogeneity of the virus or heterogeneity of the host response to the infection.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polymorphisms in HIV-1nefare associated with plasma concentration of biomarkers of endothelial activation

Mezoh

Lutchman

Cave

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Infection with HIV is associated with an increased risk of cardiovascular disease (CVD), which may be mediated by the effect of the viral proteins, Nef and Tat, on inflammation and endothelial activation. The viral genes coding for Nef and Tat contain numerous polymorphisms, which we hypothesised may be differentially associated with endothelial activation. Therefore, our aim was to assess the association of these polymorphisms with endothelial activation and inflammation in subjects infected with HIV-1. The HIV-1 nef and tat genes were sequenced from clinical isolates from 31 and 34 patients, respectively. Plasma concentration of biomarkers of endothelial activation; intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (E-selectin), monocyte chemoattractant protein-1 (MCP-1) and von Willebrand factor (vWF), and biomarkers of inflammation; tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8), were compared across Nef and Tat by varying amino acid substitutions. Analysis of HIV-1 nef gene sequences identified five polymorphisms (V16I, H40Y, T50A,H, S169N and H188Q,S) that were each significantly (p<0.05) associated with ICAM-1 plasma concentration. An additive effect of these variants on plasma ICAM-1 concentration (p=0.004 for trend), was observed. No significant associations were seen between Tat amino acid residues and plasma concentration of markers of endothelial activation and inflammation. These are the first human in vivo data that support the hypothesis that Nef polymorphisms impact endothelial function.

show abstract

“…Loss of endothelial cell (EC) integrity occurs in both PE and in HIV infection [ 25 ]. Changes in blood flow and elevation of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 and von Willebrand factor (vWF) contribute to EC injury in HIV infected patients of African ancestry [ 26 ]. Strong angiogenic factors, such as the integrins V5, V1, and V3, fibronectin, and vitronectin, are bound by the HIV-1 transactivator of transcription (Tat) protein.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of the angiotensin receptors (AT1, AT2, and AT4) in the placental bed of HIV-infected preeclamptic women of African ancestry

2023

View full text Add to dashboard Cite

The Renin-Angiotensin-Aldosterone System (RAAS) is implicated in the pathophysiology of preeclampsia (PE). There is a paucity of data on uteroplacental angiotensin receptors AT1-2 and 4. We evaluated the immunoexpression of AT1R, AT2R, and AT4R within the placental bed of PE vs. normotensive (N) pregnancies stratified by HIV status. Placental bed (PB) biopsies (n = 180) were obtained from N and PE women. Both groups were stratified by HIV status and gestational age into early-and late onset-PE. Immuno-labeling of AT1R, AT2R, and AT4R was quantified using morphometric image analysis. Immunostaining of PB endothelial cells (EC) and smooth muscle cells of spiral arteries (VSMC) displayed an upregulation of AT1R expression compared to the N group (p < 0.0001). Downregulation of AT2R and AT4R expression was observed in PE vs. N group (p = 0.0042 and p < 0.0001), respectively. AT2R immunoexpression declined between HIV+ve and HIV−ve groups, while AT1R and AT4R displayed an increase. An increase in AT1R expression was noted in the EOPE−ve/+ve and LOPE−ve/+ve compared to N−ve/N+ve. In contrast, AT2R and AT4R expression decreased in EOPE−ve/+ve and LOPE-ve/+ve compared to N−ve/N+ve. We demonstrate a significant downregulation of AT2R and AT4R with a concomitant elevated AT1R immunoexpression within PB of HIV-infected PE women. In addition, a decline in AT2R and AT4R with an increase in AT1R immunoexpression in PE, EOPE, and LOPE vs. normotensive pregnancies, irrespective of HIV status. Thus highlighting differential immunoexpression of uteroplacental RAAS receptors based on pregnancy type, HIV status, and gestational age.

show abstract

Biomarkers of Endothelial Activation in Black South African HIV-Positive Subjects are Associated with Both High Viral Load and Low CD4 Counts

Cited by 6 publications

References 51 publications

HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda

HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda

Polymorphisms in HIV-1nefare associated with plasma concentration of biomarkers of endothelial activation

Differential expression of the angiotensin receptors (AT1, AT2, and AT4) in the placental bed of HIV-infected preeclamptic women of African ancestry

Contact Info

Product

Resources

About