Novel Mechanism of Microvesicle Regulation by the Antiviral Protein Tetherin During HIV Infection

Background Microvesicles are cell membrane–derived vesicles that have been shown to augment inflammation. Specifically, monocyte‐derived microvesicles (MDMVs), which can express the coagulation protein tissue factor, contribute to thrombus formation and cardiovascular disease. People living with HIV experience higher prevalence of cardiovascular disease and also exhibit increased levels of plasma microvesicles. The process of microvesicle release has striking similarity to budding of enveloped viruses. The surface protein tetherin inhibits viral budding by physically tethering budding virus particles to cells. Hence, we investigated the role of tetherin in regulating the release of MDMVs during HIV infection. Methods and Results The plasma of aviremic HIV‐infected individuals had increased levels of tissue factor + MDMVs, as measured by flow cytometry, and correlated to reduced tetherin expression on monocytes. Superresolution confocal and electron microscopy showed that tetherin localized at the site of budding MDMVs. Mechanistic studies revealed that the exposure of monocytes to HIV‐encoded Tat triggered tetherin loss and subsequent rise in MDMV production. Overexpression of tetherin in monocytes led to morphologic changes in the pseudopodia directly underneath the MDMVs. Further, tetherin knockout mice demonstrated a higher number of circulating MDMVs and less time to bleeding cessation. Conclusions Our studies define a novel regulatory mechanism of MDMV release through tetherin and explore its contribution to the procoagulatory state that is frequently observed in people with HIV. Such insights could lead to improved therapies for individuals infected with HIV and also for those with cardiovascular disease.

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Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

Blood ◽

10.1182/blood-2009-03-210179 ◽

2010 ◽

Vol 115 (2) ◽

pp. 161-167 ◽

Cited By ~ 166

Author(s):

Nicholas T. Funderburg ◽

Elizabeth Mayne ◽

Scott F. Sieg ◽

Robert Asaad ◽

Wei Jiang ◽

...

Keyword(s):

Hiv Infection ◽

Tissue Factor ◽

Immune Activation ◽

Interleukin 6 ◽

Plasma Levels ◽

Thrombus Formation ◽

Hiv Replication ◽

Increased Risk

Abstract HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

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Triad of the Ischemic Cardiovascular Disease in People Living with HIV? Association Between Risk Factors, HIV Infection, and Use of Antiretroviral Therapy

Current Atherosclerosis Reports ◽

10.1007/s11883-018-0727-9 ◽

2018 ◽

Vol 20 (6) ◽

Cited By ~ 1

Author(s):

Hugo Ribeiro Zanetti ◽

Edmar Lacerda Mendes ◽

Antonio Carlos Palandri Chagas ◽

Maria Odila Gomes Douglas ◽

Leandro Teixeira Paranhos Lopes ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

People Living With Hiv ◽

Living With Hiv

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COVID-19 and its effects on endothelium in HIV-positive patients in sub-Saharan Africa: Cardiometabolic risk, thrombosis and vascular function (ENDOCOVID STUDY)

BMC Infectious Diseases ◽

10.1186/s12879-021-06426-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Nandu Goswami ◽

Per Morten Fredriksen ◽

Knut E. A. Lundin ◽

Chidozie Agu ◽

Simiat Olanike Elias ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Endothelial Function ◽

Hiv Infection ◽

Sub Saharan Africa ◽

System Capacity ◽

People Living With Hiv ◽

Vascular Endothelial ◽

Vascular Endothelial Function ◽

Sub Saharan

Abstract Background COVID-19 has affected almost every country in the world, especially in terms of health system capacity and economic burden. People from sub-Saharan Africa (SSA) often face interaction between human immunodeficiency virus (HIV) infection and non-communicable diseases such as cardiovascular disease. Role of HIV infection and anti-retroviral treatment (ART) in altered cardiovascular risk is questionable and there is still need to further carry out research in this field. However, thus far it is unclear, what impact the COVID-19 co-infection in people living with HIV (PLHIV), with or without therapy will have. The ENDOCOVID project aims to investigate whether and how HIV-infection in COVID-19 patients modulates the time course of the disease, alters cardiovascular risk, and changes vascular endothelial function and coagulation parameters/ thrombosis risk. Methods A total of 1026 patients will be included into this study. Cardiovascular research PLHIV with (n = 114 in each of the three recruiting centers) - or without - ART (n = 114 in each of the three recruiting centers) with COVID-19 and HIV-negative with COVID-19 (n = 114 in each of the three recruiting centers) will be carried out via clinical and biochemical measurements for cardiovascular risk factors and biomarkers of cardiovascular disease (CVD). Vascular and endothelial function will be measured by brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) assessments, and retinal blood vessel analyses, along with vascular endothelial biomarkers and cogualation markers. The correlation between HIV-infection in COVID-19 PLHIV with or without ART and its role in enhancement of cardiovascular risk and endothelial dysfunction will be assessed at admission, weekly, at discharge and, 4 weeks post-discharge (if possible). Impact of project The ENDOCOVID project aims to evaluate in the long-term the cardiovascular risk and vascular endothelial function in PLHIV thus revealing an important transitional cardiovascular phenotype in COVID-19. The study was registered under clinicaltrials.gov (NCT04709302).

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Effects of HIV Infection on Arterial Endothelial Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315435 ◽

2020 ◽

Author(s):

James H. Stein ◽

Noah Kime ◽

Claudia E. Korcarz ◽

Heather Ribaudo ◽

Judith S. Currier ◽

...

Keyword(s):

Cardiovascular Disease ◽

Endothelial Function ◽

Hiv Infection ◽

Brachial Artery ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Covariate Adjustment ◽

People Living With Hiv ◽

Hiv Serostatus ◽

Living With Hiv

Objective: To determine the effects of HIV serostatus and disease severity on endothelial function in a large pooled cohort study of people living with HIV infection and HIV− controls. Approach and Results: We used participant-level data from 9 studies: 7 included people living with HIV (2 treatment-naïve) and 4 had HIV− controls. Brachial artery flow-mediated dilation (FMD) was measured using a standardized ultrasound imaging protocol with central reading. After data harmonization, multiple linear regression was used to examine the effects of HIV− serostatus, HIV disease severity measures, and cardiovascular disease risk factors on FMD. Of 2533 participants, 986 were people living with HIV (mean 44.4 [SD 11.8] years old) and 1547 were HIV− controls (42.9 [12.2] years old). The strongest and most consistent associates of FMD were brachial artery diameter, age, sex, and body mass index. The effect of HIV+ serostatus on FMD was strongly influenced by kidney function. In the highest tertile of creatinine (1.0 mg/dL), the effect of HIV+ serostatus was strong (β=−1.59% [95% CI, −2.58% to −0.60%], P =0.002), even after covariate adjustment (β=−1.36% [95% CI, −2.46% to −0.47%], P =0.003). In the lowest tertile (0.8 mg/dL), the effect of HIV+ serostatus was strong (β=−1.90% [95% CI, −2.58% to −1.21%], P <0.001), but disappeared after covariate adjustment. HIV RNA viremia, CD4+ T-cell count, and use of antiretroviral therapy were not meaningfully associated with FMD. Conclusions: The significant effect of HIV+ serostatus on FMD suggests that people living with HIV are at increased cardiovascular disease risk, especially if they have kidney disease.

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Challenges of Cardiovascular Disease Risk Evaluation in People Living With HIV Infection

Circulation ◽

10.1161/circulationaha.118.033913 ◽

2018 ◽

Vol 137 (21) ◽

pp. 2215-2217 ◽

Cited By ~ 2

Author(s):

Andre Pascal Kengne ◽

Mpiko Ntsekhe

Keyword(s):

Cardiovascular Disease ◽

Hiv Infection ◽

Risk Evaluation ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

People Living With Hiv ◽

Living With Hiv

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Evaluation of Biochemical Markers of Cardiac Risk in ART-Treated HIV-Infected Adults in Rwanda

10.21203/rs.3.rs-1024775/v1 ◽

2021 ◽

Author(s):

Marcus Bushaku ◽

Caleb Nyamwange ◽

Arthur Kwena ◽

Marc Twagirumukiza ◽

Jean Nepo Utumatwishima ◽

...

Keyword(s):

Cardiovascular Disease ◽

Hiv Infection ◽

Total Cholesterol ◽

Biochemical Markers ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Cardiac Risk ◽

People Living With Hiv ◽

African Countries ◽

Cvd Risk

Abstract Background Life expectancy of people living with HIV infection has improved due to access to antiretroviral therapy (ART) in Rwanda like other African countries. However, both HIV infection and use of ART are associated with cardiovascular disease (CVD) risks, due to adverse changes in some biochemical markers, causing dyslipidemia and other metabolic imbalances. The CVD risk associated with metabolic biomarkers that may affect cardiac function with use of the ART, has not been well characterized in Rwanda. We evaluated the association between the use and duration of ART and abnormal changes in biochemical markers of CVD risk among HIV infected adults in Rwanda. Methods Participants were enrolled from HIV Clinics Public Health Centers in a cross-sectional study in Kigali. A total of 150 participants between 18-45 years included 30 HIV-Uninfected (HIV-) and 120 HIV-infected (HIV+) adults. Among the HIV+ adults, 40 participants were ART-naïve. Data were collected on health-related behaviors and biochemical markers of CVD risk. We compared changes in CVD-related biochemical markers between HIV-, HIV+ ART-naïve and HIV+ on ART treatment groups. Results Majority of participants were women (60%), and HIV- were younger (35±6 vs. 31±6 years). We observed differences in levels of cholesterol and triglycerides in HIV+ ART-treated and HIV+ ART-naïve groups. Total cholesterol and triglycerides were associated with use of ART. Serum triglycerides were lower in HIV+ ART-naïve compared to HIV+ on ART treatment (61.20±18.30 mg/dl vs. 85.00±38.30 mg/dl; p< 0.01). While total cholesterol was higher in HIV+ on ART than HIV+ ART-naïve (136.00±45.00 mg/dl vs. 119.00±36.00 mg/dl; p<0.04), HDL-C was associated with longer exposure to ART (68.70±30.00 mg/dl vs. 54.90±25.70 mg/dl; p=0.02) among HIV+ on ART for 0-6 months and 7-12 months respectively. Conclusion Changes in serum total cholesterol and triglycerides were associated with use of ART. Although these changes were within the upper limits of normal ranges, our findings suggest early increases in both biochemical biomarkers of cardiac risk associated. These findings underscore the need for early evaluation of lipid profiles as biomarkers of cardiovascular disease risk, to effectively monitor how ART may contribute to cardiovascular disease and deter treatment programs in African countries.

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Cloning of the Rat Tissue Factor cDNA and Promoter: Identification of a Serum-response Region

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650646 ◽

1996 ◽

Vol 76 (05) ◽

pp. 697-702 ◽

Cited By ~ 10

Author(s):

Olivier Taby ◽

Claire-Lise Rosenfield ◽

Vladimir Bogdanov ◽

Yale Nemerson ◽

Mark B Taubman

Keyword(s):

Tissue Factor ◽

General Structure ◽

Amino Acid Sequences ◽

Proximal Promoter ◽

Striking Similarity ◽

Upstream Sequence ◽

Tf Gene ◽

Rat Tissue ◽

High Degree ◽

Transcriptional Elements

SummaryTissue factor (TF) initiates coagulation and its expression in vascular smooth muscle cells (VSMC) likely plays a role in the propagation of arterial thrombosis. We report cloning the cDNA and proximal promoter region of the rat TF gene. While maintaining the general structure and organization of the TF molecule, there is a surprising divergence (≈ 18%) between the derived amino acid sequences of the rat and mouse TF. In contrast, there is striking similarity (90%) in the 5’ untranslated regions. High levels of basal promoter activity were seen in rat VSMC with constructs containing 106 bp of sequence downstream from the putative transcription start site and 426 to 103 bp of upstream sequence. Deletion of the sequence from −103 to −79, containing a single SP1 site, removed virtually all of the basal and serum-induced activity. Removal of the NFkB site or two additional upstream SP1 sites had little effect on serum responsiveness. Removal of the 5’ untranslated region abolished most of the basal activity of the TF promoter, suggesting that its high degree of conservation may be due to the presence of transcriptional elements critical for TF expression in rodent VSMC.

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Predominance of PVL-negative community-associated methicillin-resistant Staphylococcus aureus sequence type 8 in newly diagnosed HIV-infected adults, Tanzania

European Journal of Clinical Microbiology & Infectious Diseases ◽

10.1007/s10096-021-04160-2 ◽

2021 ◽

Author(s):

Joel Manyahi ◽

Sabrina J. Moyo ◽

Said Aboud ◽

Nina Langeland ◽

Bjørn Blomberg

Keyword(s):

Staphylococcus Aureus ◽

Hiv Infection ◽

Diffusion Method ◽

Molecular Characteristics ◽

People Living With Hiv ◽

Newly Diagnosed ◽

Beta Lactam ◽

Disk Diffusion Method ◽

Methicillin Resistant ◽

Inducible Clindamycin Resistance

AbstractDifficult-to-treat infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are of concern in people living with HIV infection as they are more vulnerable to infection. We aimed to identify molecular characteristics of MRSA colonizing newly diagnosed HIV-infected adults in Tanzania. Individuals newly diagnosed with HIV infection were recruited in Dar es Salaam, Tanzania, from April 2017 to May 2018, as part of the randomized clinical trial CoTrimResist (ClinicalTrials.gov identifier: NCT03087890). Nasal/nasopharyngeal isolates of Staphylococcus aureus were susceptibility tested by disk diffusion method, and cefoxitin-resistant isolates were characterized by short-reads whole genome sequencing. Four percent (22/537) of patients carried MRSA in the nose/nasopharynx. MRSA isolates were frequently resistant towards gentamicin (95%), ciprofloxacin (91%), and erythromycin (82%) but less often towards trimethoprim-sulfamethoxazole (9%). Seventy-three percent had inducible clindamycin resistance. Erythromycin-resistant isolates harbored ermC (15/18) and LmrS (3/18) resistance genes. Ciprofloxacin resistance was mediated by mutations of the quinolone resistance-determining region (QRDR) sequence in the gyrA (S84L) and parC (S80Y) genes. All isolates belonged to the CC8 and ST8-SCCmecIV MRSA clone. Ninety-five percent of the MRSA isolates were spa-type t1476, and one exhibited spa-type t064. All isolates were negative for Panton-Valentine leucocidin (PVL) and arginine catabolic mobile element (ACME) type 1. All ST8-SCCmecIV-spa-t1476 MRSA clones from Tanzania were unrelated to the globally successful USA300 clone. Carriage of ST8 MRSA (non-USA300) was common among newly diagnosed HIV-infected adults in Tanzania. Frequent co-resistance to non-beta lactam antibiotics limits therapeutic options when infection occurs.

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MicroRNA as Biomarkers for Platelet Function and Maturity in Patients with Cardiovascular Disease

Thrombosis and Haemostasis ◽

10.1055/s-0041-1730375 ◽

2021 ◽

Author(s):

Oliver Buchhave Pedersen ◽

Erik Lerkevang Grove ◽

Steen Dalby Kristensen ◽

Peter H. Nissen ◽

Anne-Mette Hvas

Keyword(s):

Cardiovascular Disease ◽

Platelet Function ◽

Assessment Tool ◽

Platelet Reactivity ◽

Thrombus Formation ◽

Quality Assessment Tool ◽

Treatment And Prevention ◽

Increased Risk ◽

Meta Analyses ◽

Potential Use

AbstractPatients with cardiovascular disease (CVD) are at increased risk of suffering myocardial infarction. Platelets are key players in thrombus formation and, therefore, antiplatelet therapy is crucial in the treatment and prevention of CVD. MicroRNAs (miRs) may hold the potential as biomarkers for platelet function and maturity. This systematic review was conducted using the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To identify studies investigating the association between miRs and platelet function and maturity in patients with CVD, PubMed and Embase were searched on October 13 and December 13, 2020 without time boundaries. Risk of bias was evaluated using a standardized quality assessment tool. Of the 16 included studies, 6 studies were rated “good” and 10 studies were rated “fair.” In total, 45 miRs correlated significantly with platelet function or maturity (rho ranging from –0.68 to 0.38, all p < 0.05) or differed significantly between patients with high platelet reactivity and patients with low platelet reactivity (p-values ranging from 0.0001 to 0.05). Only four miRs were investigated in more than two studies, namely miR-223, miR-126, miR-21 and miR-150. Only one study reported on the association between miRs and platelet maturity. In conclusion, a total of 45 miRs were associated with platelet function or maturity in patients with CVD, with miR-223 and miR-126 being the most frequently investigated. However, the majority of the miRs were only investigated in one study. More data are needed on the potential use of miRs as biomarkers for platelet function and maturity in CVD patients.

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