thromboplastin and HIV-Infections

Venous thromboembolic disease often arises as a complication of another pathological condition and/or triggering event. Infectious diseases result from both the direct action of the pathogens themselves and their effect on the immune system. The resulting inflammatory process and the coagulation and fibrinolysis processes share common pathways, explaining why infection is associated with thrombosis. In this brief overview, besides certain chronic infectious diseases, we also consider some acute infections, as the mechanisms are likely to be similar, particularly in the initial infective stage or the more acute episodes of a chronic infection. The infectious agent can be viral, bacterial, fungal, or parasitic. However, the literature on the link between infections and venous thromboembolism (VTE) is uneven, favoring infections that are found in more developed countries where physicians have access to VTE diagnostic tools. Thus, large epidemiological studies in this field are restricted to a limited number of the common chronic infectious diseases such as tuberculosis, while for other infections, particularly parasitic and fungal infections, the link with VTE is only evoked in a few scattered case reports.

Topics: Cell-Derived Microparticles; Chronic Disease; Developed Countries; Developing Countries; Disease Susceptibility; Endothelium, Vascular; HIV Infections; Humans; Infections; Inflammation; Macrophages; Models, Biological; Risk; Thrombophilia; Thromboplastin; Tuberculosis; Venous Thromboembolism

Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.. NCT 01543958.

Topics: Adult; Bacterial Translocation; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; HIV Infections; Humans; Lipopolysaccharide Receptors; Lipopolysaccharides; Lipoproteins, LDL; Male; Middle Aged; Polyamines; Sevelamer; Thromboplastin; Treatment Outcome; Young Adult

HIV-1 infection is associated with multiple procoagulant changes and increased thrombotic risk. Possible mechanisms for this risk include heigthened expression of procoagulant tissue factor (TF) on circulating monocytes, extracellular vesicles, and viral particles and/or acquired deficiency of protein S (PS), a critical cofactor for the anticoagulant protein C (PC). PS deficiency occurs in up to 76% of people living with HIV-1 (PLWH). As increased ex vivo plasma thrombin generation is a strong predictor of mortality, we investigated whether PS and plasma TF are associated with plasma thrombin generation.. We analyzed plasma samples from 9 healthy controls, 17 PLWH on first diagnosis (naive), and 13 PLWH on antiretroviral therapy (ART). Plasma thrombin generation, total and free PS, PC, C4b-binding protein, and TF activity were measured.. We determined that the plasma thrombin generation assay is insensitive to PS, because of a lack of PC activation, and developed a modified PS-sensitive assay. Total plasma PS was reduced in 58% of the naive and 38% of the ART-treated PLWH samples and correlated with increased thrombin generation in the modified assay. Conversely, plasma TF was not increased in our patient population, suggesting that it does not significantly contribute to ex vivo plasma thrombin generation.. These data suggest that reduced total plasma PS contributes to the thrombotic risk associated with HIV-1 infection and can serve as a prothrombotic biomarker. In addition, our refined thrombin generation assay offers a more sensitive tool to assess the functional consequences of acquired PS deficiency in PLWH.

Topics: Biomarkers; HIV Infections; Humans; Protein S; Thrombin; Thromboplastin

Morbidity and mortality associated with HIV infection is immune-mediated, and an understanding of HIV immunology will be beneficial in the management of HIV infectionOBJECTIVE: The objective of this research was to measure the levels of TNF-α, IL-6 and IFN-γ in asymptomatic HIV patients and non-HIV subjects, as well as their relationship with CD4 count.. Blood samples were collected from 173 subjects, consisting of 125 asymptomatic HIV patients (44 HAART-naïve and 81 on HAART) and 48 non-HIV subjects. The IFN-, IL-6, and TNF- levels in the blood were determined using enzyme-linked immunosorbent assays, and the CD4 count of all participants was determined using flow cytometry.. Regardless of treatment status, the IFN-γ levels of non-HIV subjects were significantly higher than those of HIV patients (p< 0.001). The opposite was true for IL-6, as the levels of IL-6 in non-HIV subjects were significantly lower than those in HAART-naïve HIV patients (p< 0.001) and those on HAART (p< 0.01). TNF-α levels did not differ between HIV patients and their non-HIV counterparts. Generally, the levels of these cytokines was not affected (p> 0.05) by immunosuppression (measured by CD4 count < 200 cells/μL) and there was no significant correlation between CD4 count and these cytokines (p> 0.05).. In conclusion, asymptomatic HIV infection decreased IFN-γ, increased IL-6, and had no effect on TNF-α levels, regardless of treatment status. Immunosuppression had no impact on these cytokine levels, and there was no relationship between them and CD4 counts.

Topics: Cytokines; HIV Infections; Humans; Interferon-gamma; Interleukin-6; Necrosis; Nigeria; Thromboplastin; Tumor Necrosis Factor-alpha

We evaluated the roles of biomarkers of immune activation with carotid intima-media thickness (CIMT) progression in treated HIV infection.. Longitudinal observational study of 118 treated and virologically suppressed individuals.. We measured biomarkers of immune activation at baseline using cryopreserved samples. CIMT was measured at baseline and longitudinally using high-resolution ultrasound. Linear regression was used to estimate biomarker associations with CIMT progression, and logistic regression was used to model plaque progression.. The median duration of follow-up was 2.0 years. The median annual rate of change in mean CIMT was 6.0%. Rates of progression were more rapid in the bifurcation (5.6%/year, P = 0.006) and internal (6.5%/year, P = 0.0008) than common CIMT (4.3%/year). Incident plaque occurred in 13 of the 52 individuals without baseline plaque. In multivariable adjusted analysis, plasma tissue factor and monocyte chemoattractant protein-1 were associated with more rapid common CIMT progression (0.058 mm/year, P = 0.0004 and 0.067 mm/year, P = 0.017; all estimates per doubling). CD8 T-cell count and percentage of HLA-DRCD38CD8 T cells were associated with more rapid internal CIMT progression (0.10 mm/year, P = 0.008 and 0.054 mm/year, P = 0.045). CD8 T-cell count was also associated with 0.068 mm/year more rapid mean CIMT progression (P = 0.011). Each 10% increase in CD4 T-cell count at baseline was associated with a 34% reduced odds of plaque progression (P = 0.018).. Residual immune activation and plasma tissue factor are independently associated with CIMT progression in treated HIV infection. Interventions targeting coagulation and inflammatory pathways to reduce cardiovascular disease risk in HIV merit additional investigations.

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Disease Progression; Female; HIV Infections; Humans; Longitudinal Studies; Male; Middle Aged; Plaque, Atherosclerotic; Plasma; Risk Factors; Thromboplastin

Topics: Arteries; Carotid Intima-Media Thickness; Disease Progression; HIV Infections; Humans; Thromboplastin

Circulating CD8+ T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8+ T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8+ T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect.

Topics: Blood Coagulation; CD8-Positive T-Lymphocytes; Cells, Cultured; Endothelial Cells; HIV Infections; Humans; Monocytes; Receptors, Antigen, T-Cell; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Adult; Anti-HIV Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Blood Coagulation; Cardiovascular Diseases; Case-Control Studies; Cell Proliferation; Cross-Sectional Studies; Female; Forkhead Transcription Factors; HIV Infections; Humans; Lipids; Lymphocyte Activation; Macrophage Activation; Male; Matrix Attachment Region Binding Proteins; Membrane Proteins; Middle Aged; Monocytes; Receptors, Cell Surface; Risk Factors; T-Lymphocyte Subsets; Thromboplastin

Expression of tissue factor (TF) on the surface of activated monocytes may trigger thrombosis, leading to clotting risk, inflammation, and atherosclerosis. TF-positive microparticles (MP-TF) represent a functionally active form of TF that may be promulgated by long-term HIV infection. We hypothesized that greater MP-TF activity is associated with carotid artery plaque in HIV+ women.. In a case-control study nested within the Women's Interagency HIV Study (WIHS), eligible HIV+ participants underwent B-mode carotid artery ultrasound at 2 study visits occurring 7 years apart. Cases were defined by the presence of at least 1 carotid artery plaque assessed at either visit. Cases were matched 1:2 to controls who were found not to have carotid artery plaques.. Conditional logistic regression estimated the association of MP-TF activity with the presence of carotid artery plaque, adjusting for demographic and behavioral characteristics, HIV-related factors, cardiometabolic risk factors, and serum inflammation biomarkers (high-sensitivity C-reactive protein, IL-6, sCD14, sCD163, Gal-3, and Gal-3BP).. Elevated MP-TF activity (>0.537 pg/mL) was found to be significantly associated with greater odds of plaque (adjusted odds ratio 3.86, 95% confidence interval: 1.06 to 14.07, P = 0.04). The association was attenuated after further adjustment for IL-6 but was unaffected by adjustment for other biomarkers including those denoting monocyte activation.. Our findings suggest a link among HIV infection, innate immune system perturbation, coagulation, and atherosclerosis.

Topics: Adult; Carotid Stenosis; Case-Control Studies; Female; HIV Infections; Humans; Middle Aged; Thromboplastin; Ultrasonography

Objectives To determine the association of the markers of monocyte activation and arterial stiffness among HIV-infected antiretroviral therapy (ART)-naïve men. Methods Sixty HIV-infected ART-naïve men and 20 HIV-uninfected male controls without symptoms or history of cardiovascular disease were recruited. Pulse wave velocity (PWV) were used as the marker of arterial stiffness and determined using a pulse pressure analyzer. The percentage of CD16-expressing monocytes was used as a marker of monocyte activation. Plasma neopterin concentration, one of the monocyte/macrophage activation markers and plasma tissue factor (TF), the coagulation marker in response to inflammatory stimuli, were also analyzed. Multivariate analyses were used to explore the association of the percentage of CD16-expressing monocytes with arterial stiffness in HIV-infected men. Results HIV-infected ART-naïve men demonstrated significantly higher PWV (1252.8 ± 161.6 vs.1159.2 ± 108.3 cm/s, p = 0.018). The percentage of CD16-expressing monocytes was significantly higher in HIV-infected men comparing male controls (23.4 ± 6.0% vs. 19.6 ± 4.6%, p = 0.012). Plasma concentrations of neopterin (0.91 vs. 0.64 ng/ml), p < 0.001) and TF (5.29 vs. 4.43 pg/ml, p = 0.04) were higher in HIV-infected men comparing controls. In the multivariate model for PWV among HIV-infected men, the percentage of CD16-expressing monocytes (p = 0.023) and age (p = 0.017) were significantly associated with PWV. HIV viral load, CD4 count, percentage of CD8+CD38+T cells and percentage of CD8+HLA-DR+ T cells were not associated with PWV. Discussion Higher level of monocyte activation marker is associated with higher level of arterial stiffness in ART naïve HIV-infected men. HIV viral load, CD4 count, and the markers of CD8 T cell activation were unrelated to PWV.

Topics: Adolescent; Adult; Age Factors; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; GPI-Linked Proteins; HIV Infections; Humans; Male; Middle Aged; Monocytes; Neopterin; Pulse Wave Analysis; Receptors, IgG; Thromboplastin; Vascular Stiffness; Viral Load; Young Adult

HIV infection is associated with an increased risk of cardiovascular disease in connection with atherosclerosis and thromboembolic complications. The pathogenesis of atherosclerosis is still unclear in this group of patients. Studies on pathogenesis of atherosclerosis in the general population emphasize the role of the extrinsic pathway of blood coagulation, particularly the tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The effect of persistent activation of the immune system on enhanced expression of TF on the surface of monocytes in subjects infected with HIV is known to be correlated with the level of HIV RNA in blood serum.. The aim of this study was to evaluate the concentration of TF and its inhibitor TFPI in blood plasma, the impact of traditional and non-traditional cardiovascular risk factors on their concentration and the impact of both markers of haemostasis on the severity of subclinical atherosclerosis as assessed by the intima-media measurement of the carotid artery in HIV infected patients.. The study included 121 HIV-infected people with known clinical, immunological and virological status. The control group consisted of 42 healthy individuals, selected in terms of age and sex.. Higher concentrations of TF occurred in HIV-infected patients with a low current plasma HIV RNA level, nadir CD4+ T-cell count and longer duration of cumulative antiretroviral treatment. In multivariate analysis, it was the length of cumulative NRTI treatment that impacted on the concentration of TF. The determinants of cardiovascular disease (CVD) risk factors and inflammatory markers did not show any effect on the concentrations of TF. The TFPI level in HIV-infected patients was significantly higher than in the control group and was negatively correlated with the current level of HIV RNA and nadir CD4+ T-cell count, being higher in patients subjected to antiretroviral treatment. It was shown that the higher the cardiovascular risk and the higher the levels of total cholesterol, low-density lipoprotein cholesterol (LDL) and non-high-density lipoprotein cholesterol (non-HDL), the higher the concentrations of TFPI observed. The levels of TF and TFPI were positively correlated with carotid intima media thickness (cIMT); in the multivariate analysis, TF, non-HDL cholesterol and lifetime smoking (pack-years) independently affected the growth of cIMT. A similar effect on cIMT was demonstrated by TFPI.

Topics: Adult; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Female; HIV; HIV Infections; Humans; Inflammation Mediators; Linear Models; Lipoproteins; Male; Middle Aged; Multivariate Analysis; Risk Factors; RNA, Viral; Thromboplastin

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.

Topics: Animals; Anti-Retroviral Agents; Antibodies, Viral; Blood Coagulation; Blood Coagulation Disorders; Chlorocebus aethiops; Chronic Disease; Cytokines; HIV Infections; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharide Receptors; Lipopolysaccharides; Monocytes; Receptor, PAR-1; Signal Transduction; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Thromboplastin

Tissue factor (TF) is a protein that mediates the initiation of the coagulation cascade. TF expression is increased in patients with poorly-controlled HIV, and may be associated with increased immune activation that leads to cardiovascular morbidity. The role of TF in immune activation in liver disease in hepatitis C virus (HCV)-monoinfection and HIV/HCV-coinfection has not been explored.. Fifty-nine patients were stratified: A) HIV-monoinfection (N = 15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N = 15), C) HIV/HCV-coinfection with CHC (N = 14), and D) HIV/HCV-seropositive with cleared-HCV (N = 15). All HIV+ patients had undetectable HIV viremia. Whole blood was collected for CD4/CD8 immune activation markers by flow cytometry and plasma was assayed for microparticle TF (MPTF) activity. Subjects underwent transient elastography (TE) to stage liver fibrosis. Undetectable versus detectable MPTF was compared across strata using Fisher's Exact test.. MPTF activity was more frequently detected among patients with HCV-monoinfection (40%), compared to HIV-monoinfection and HIV/HCV-seropositive with cleared HCV (7%) and HIV/HCV-coinfection with CHC (14%) (p = 0.02). Mean TE-derived liver stiffness score in kPa was higher in patients with detectable MPTF (12.4 ± 8.5) than those with undetectable MPTF (6.4 ± 3.0) (p = 0.01). Mean CD4 + HLADR+ and CD4 + CD38-HLADR+ expression were higher in those with detectable MPTF (44 ± 9.8% and 38 ± 8.7%, respectively) than those with undetectable MPTF (36 ± 11% and 31 ± 10.4% respectively) (p = 0.05 and 0.04 respectively).. HCV-monoinfection and HIV/HCV-coinfection with CHC were associated with MPTF activity. MPTF activity is also associated with advanced liver fibrosis and with CD4 + HLADR+ immune activation.

Topics: Adult; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Coinfection; Cross-Sectional Studies; Female; Flow Cytometry; Hepatitis C; Hepatitis C, Chronic; HIV Infections; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Thromboplastin; Ultrasonography

Activation of coagulation pathways may contribute to risk for non-AIDS-related conditions among HIV-positive patients. Tissue factor (TF)-dependent procoagulant activity on circulating microparticles (MP-TF) in the plasma of 163 HIV-positive participants, both untreated and treated, with viral suppression was measured. MP-TF activity was 39% lower among treated versus untreated participants (P < 0.001), which persisted in adjusted models (-36%, P = 0.03). Among treated participants, MP-TF activity correlated modestly with D-dimer (r = 0.24, P = 0.01), von Willebrand factor (r = 0.36, P < 0.001), and interleukin-6 (r = 0.20, P = 0.04) levels. Future research should focus on mechanisms driving residual functional TF activity and whether these alterations have clinical consequences for non-AIDS-defining complications.

Topics: Adult; Anti-HIV Agents; Blood Coagulation; Blood Coagulation Tests; C-Reactive Protein; Cell-Derived Microparticles; Female; HIV Infections; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Thromboplastin; von Willebrand Factor

HIV-1-infected patients have an increased risk for atherothrombosis and cardiovascular disease, but the mechanism behind these risks is poorly understood. We have previously reported that expression of tissue factor (TF) on circulating monocytes is increased in persons with HIV infection and that TF expression is related to immune activation, to levels of HIV in plasma, and to indices of microbial translocation. In this study, we explore the activation state of platelets in HIV disease.. Here, using flow cytometry-based assays, we measured platelet and platelet microparticle (PMP) activation in samples from HIV-1-infected donors and controls.. Platelets and PMPs from HIV-1-infected patients are activated (as reflected by expression of CD62 P-selectin) and also more frequently expressed the procoagulant TF than did platelets and PMPs obtained from controls. Expression of these proteins was directly related to expression of TF on monocytes, to markers of T-cell activation (CD38 and HLA-DR), and to plasma levels of soluble CD14, the coreceptor for bacterial lipopolysaccharride. Platelet and microparticle expression of TF was not related to plasma levels of HIV but expression of P-selectin was related to plasma levels of HIV; neither TF nor P-selectin expression was related to CD4 T-cell count.. Platelets and microparticles are activated in HIV infection, and this activated phenotype may contribute to the increased risk for cardiovascular and thrombotic events in this population although a role for other confounding cardiovascular risks cannot be completely excluded.

Topics: ADP-ribosyl Cyclase 1; Adult; Aged; Blood Platelets; CD4 Lymphocyte Count; Cell-Derived Microparticles; Female; Flow Cytometry; HIV Infections; HLA-DR Antigens; Humans; Lipopolysaccharide Receptors; Lymphocyte Activation; Male; Membrane Glycoproteins; Middle Aged; Monocytes; P-Selectin; Platelet Activation; Thromboplastin; Up-Regulation; Young Adult

The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.

Topics: Acute Coronary Syndrome; Adult; Aged; Female; Flow Cytometry; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immunophenotyping; Interleukin-6; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Middle Aged; Monocytes; Receptors, IgG; Thromboplastin; Young Adult

Cytomegalovirus is associated with hypercoagulability, and is reported to increase the risk of venous thrombosis in human immunodeficiency virus (HIV)-infected patients. Progression to AIDS, however, is also associated with hypercoagulability and venous thrombosis, and may result in more comorbidities, such as reactivation of cytomegalovirus. It is therefore unknown whether active cytomegalovirus in HIV infection results in a procoagulant state or whether hypercoagulability is the result of HIV infection itself. In this cross-sectional study of 104 consecutive HIV-infected patients, active cytomegalovirus infection was associated with hypercoagulability independently of stage of HIV disease. This finding may deserve attention in preventative recommendations for use of thromboprophylaxis in HIV-infected patients.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; CD4-Positive T-Lymphocytes; Cross-Sectional Studies; Cytomegalovirus; Cytomegalovirus Infections; Female; HIV Infections; Humans; Lymphocyte Count; Male; Middle Aged; Protein S; Thrombophilia; Thromboplastin; Thrombosis

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.

Topics: Adult; Biomarkers; Cells, Cultured; Female; Fibrin Fibrinogen Degradation Products; Flagellin; Gene Expression Regulation; HIV; HIV Infections; Humans; Interleukin-6; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Monocytes; Risk Factors; Thromboplastin; Thrombosis; Virus Replication

There have been increasing reports of acute coronary thrombotic events in patients with HIV. Although these clinical events have been attributed primarily to dyslipidemia associated with protease inhibitor therapy, autopsy studies in children with HIV suggest the presence of an underlying arteriopathy. This study demonstrates that the HIV envelope protein, gp120, activates human arterial smooth muscle cells to express tissue factor, the initiator of the coagulation cascade. The induction of tissue factor by gp120 is mediated by two biologically relevant coreceptors for HIV infection, CXCR4 and CCR5, and is also dependent on the presence of functional CD4. Induction of tissue factor by gp120 requires activation of mitogen-activating protein kinases, activation of protein kinase C, and generation of reactive oxygen species, signaling pathways that have protean effects on smooth muscle cell physiology. The activation of smooth muscle cells by gp120 may play an important role in the vascular, thrombotic, and inflammatory responses to HIV infection.

Topics: CD4 Antigens; Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Coronary Thrombosis; HIV Envelope Protein gp120; HIV Infections; Humans; Ligands; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Protein Kinase C; Reactive Oxygen Species; Receptors, CCR5; Receptors, CXCR4; Recombinant Proteins; Thromboplastin

With the use of the principal neutralizing determinant (PND) peptide-based ELISA to measure anti-PND antibodies that specifically bound synthetic peptides derived from HIVIIIB, HIVMN, HIVRF, HIVSC, HIVWJM-2, HIVAf1l.con, or HIVAf2.con, type-specific antibodies to the HIVMN peptide were studied in 350 serum specimens from Japanese with hemophilia A who had been injected with known unheated factor VIII concentrates until 1985 and had been infected with HIV-1 subtype B. These antibodies were not found in any of the seronegative sera of hemophiliacs, patients with autoimmune diseases, or normal healthy controls. Further, all hemophiliacs rapidly progressing to AIDS and death among the 95 hemophiliacs in a restricted Nara area had antibody titers of less than 20 and their low levels preceded the rapid progression to the disease state. In contrast, slowly progressing hemophiliacs maintained an antibody titer of more than 100 from the initial stages of viral infection and remained asymptomatic. Sequence analysis of the V3 regions of HIV-1 indicated that the hemophiliacs who maintained a high anti-PNDMN antibody level showed a conserved MN sequence. In contrast, the HIV-infected hemophiliacs with nonreactivity in the ELISA showed sequence changes in the neutralizing epitopes of HIVMN. The dynamic of the serum anti-PNDMN antibody titer appear to be a characteristic indicator of the progression of the HIV-infected status in Japanese hemophiliacs seropositive for HIV-1.

Topics: Adult; Amino Acid Sequence; Consensus Sequence; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Hemophilia A; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Japan; Male; Middle Aged; Molecular Sequence Data; Neutralization Tests; Peptide Fragments; Prevalence; Thromboplastin

Topics: CD4-Positive T-Lymphocytes; HIV Infections; Humans; Leukocyte Count; Lipopolysaccharides; Monocytes; RNA, Messenger; Thromboplastin