Activation In HIV-infected Patients Research Articles

Enzymes of purine metabolism — biomarkers for the diagnostics of tuberculous pleurisy in patients with HIV infection

The objective of the study was to evaluate the information content of determining the activity of adenosine deaminase and adenosine deaminase-2 in the diagnosis of tuberculous pleurisy in patients with HIV infection.Materials and methods. A total of 378 patients with pleural effusion were retrospectively examined. In 215 cases, tuberculous pleurisy was detected (TP); and 163 patients had non-tuberculous pleural effusion (non-TP). As much as 27 patients in the TP group were HIV co-infected (TP/HIV+), the remaining 188 patients were HIV — negative (TP/HIV–). In all the patients, the activity of total adenosine deaminase (ADA) and its isoenzymes (ADA-1 and ADA-2) in the pleural fluid was determined.Results and discussion. In the TP group, the activity of total ADA (95.5 [67.7; 115.4] versus 82.0 [59.6; 100.0] U/L, p=0.1), ADA-1 (14.2 [5.8; 20.5] versus 12.1 [6.1; 23.7] U/L, p=0.9) and ADA-2 (78,1 [38.1; 93.1] versus 62.4 [35.4; 82.2] U/L, p=0,1) did not depend on HIV status. The activity of these indicators was determined above the threshold level — total ADA in 96.3% and 95.2%, ADA-1 in 25.9% and 30.8% and ADA-2 in 92.6% and 83.3% of cases in the «TP/HIV+» and «TP/HIV–» groups, respectively. A negative correlation between ADA-1 activity and HIV viral load in the group of patients with tuberculous pleurisy and HIV infection (r=–0.45; p=0.008), as well as in the subgroup of TP/HIV+ patients who received (r=–0.9; p=0.008) and in those who didn’t receive ART (r=–0.47; p=0.04) was obtained. Our results show that a total ADA activity increase in the patients with tuberculous pleurisy, regardless of patients’ HIV status, occur due to ADA-2. Thus, the increase in activity of total ADA and ADA-2 in our study was caused by active tuberculosis, not by the presence or absence of HIV co-infection. Also, the ADA-2 activity in HIV-infected patients is likely consistent with ADA-2 important role in cellular immune responses.Conclusion. Our data indicate the participation of purine metabolism enzymes in the pathogenesis of HIV infection. At the same time, adenosine deaminase activity is not a specific biomarker of individual changes characteristic of HIV infection. The study results suggest that the total adenosine deaminase and adenosine deaminase-2 activity increase is a valuable and diagnostically significant marker of tuberculous pleurisy in HIV-infected patients. The value of adenosine deaminase and adenosine deaminase-2 activity remains high even in the patients having severe immunosuppression, which allows them to be actively used for rapid diagnostics and hence, early TB therapy initiation.

Characterization of the Intestinal Fungal Microbiome in HIV and HCV Mono-Infected or Co-Infected Patients.

Intestinal mycobiome dysbiosis plays an important role in the advancement of HIV- and HCV-infected patients. Co-infection with HCV is an important risk factor for exacerbating immune activation in HIV-infected patients, and gut fungal microbial dysbiosis plays an important role. However, no systematic study has been conducted on the intestinal fungal microbiome of HIV/HCV co-infected patients to date. Patients infected with HIV and HCV, either alone or in combination, and healthy volunteers were included. Stool samples were collected for fungal ITS sequencing and for further mycobiome statistical analysis. We found that the abundance of fungal species significantly decreased in the HIV/HCV co-infection group compared to in the healthy control group, while no significant differences were found in the mono-infection groups. Low-CD4 + T-cell patients in the HIV group and high-ALT-level patients in the HCV group were discovered to have a more chaotic fungal community. Furthermore, the opportunistic pathogenic fungal profiles and fungal inter-correlations in the co-infection group became less characteristic but more complicated than those in the mono-infection groups. Intestinal fungal dysregulation occurs in HIV- and HCV-infected patients, and this dysregulation is further complicated in HIV/HCV co-infected patients.

Special features of interferonlambda contents in blood serum of the patients with HIV infection

Studies in HIV infection remain an important issue for modern medicine, which, becomes controlled due to widespread usage of antiretroviral therapy. At the same time, however, it cannot be cured completely, and there is a number of “white spots” in understanding immunopathogenesis of disorders complicating this disease. The in-depth studies of interferon system, in particular from the lambda family, are desirable, because of their antiviral activity in HIV-infected patients. The aim of our study was to evaluate the content of interferons-lambda: IFNλ1 (IL-29) and IFNλ3 (IL-28B) in patients with HIV infection.Blood serum of 120 patients with HIV infection (average age 49.7±6.2 years) who were treated in the outpatient setting at the Center for AIDS Prevention and Control of Regional Clinical Hospital No. 2 in Vladivostok was subjected to laboratory testing. HIV infection 4A was the main clinical diagnosis in all the patients, i.e., the stage of secondary diseases, remission phase on the background of antiretroviral therapy (ARVT). In 52 patients, chronic viral hepatitis C was found as a concomitant disease. The content of IFNλ1 (IL-29) and IFNλ3 (IL-28B) in venous blood serum was determined by ELISA technique using a “Multiscan” analyzer. The ELISA reagents were from RD systems, catalog numbers DY5259; DY7246.In the groups of patients with HIV infection, both with and without viral hepatitis C, the levels of IFNλ1 (IL-29) and IFNλ3 (IL-28B) were significantly reduced in comparison with control group. When comparing the IFN values between the groups, a more pronounced decrease in IFNλ1 (IL-29) was revealed among the patients with viral hepatitis C. When analyzing the level of IFNλ3 (IL-28B), an opposite pattern was observed, i.e., its values in the patients with HIV infection and viral hepatitis C were higher than in the group without hepatitis, but still did not reach appropriate values of the control group. Based on the data on IFNλ3 (IL-28B) antiviral effect upon HIV transmission via macrophages One may assume that induction and maintenance of higher type 3 interferon levels can favorably affect the course of HIV infection. The registered changes in IFNλ1 (IL-29) and IFNλ3 (IL-28B) levels in the patients with HIV and HCV suggest some viral effect upon innate immunity characterized by multidirectional changes, depending on presence or absence of hepatitis C virus. The studies of changes in innate immunity and role of type 3 interferons may extend our knowledge on the interaction between the human body and HIV, and will promote preventive measures and rehabilitation in the patients with HIV infection.

Platelet activation in adult HIV-infected patients on antiretroviral therapy: a systematic review and meta-analysis

BackgroundAntiretroviral therapy (ART) alters platelet reactivity, and as a consequence, patients living with HIV may be at an increased risk of cardiovascular disease (CVD). The current evidence on platelet activation levels in patients with HIV remains inconclusive. We therefore aimed to systematically synthesise evidence on the association of platelet activation in HIV-infected patients on successful treatment.MethodsElectronic databases were searched from inception until November 2019. Studies were included if the primary or secondary outcome of the study was to assess platelet activation in HIV-infected patients on ART. The primary outcome of this review included the levels of platelet activation. The pooled effect estimates were calculated using a random-effects meta-analysis model.ResultsWe identified 30 studies comprising of 2325 participants. The pooled estimates showed elevated levels of platelet activation in treatment-naïve HIV-infected patients compared to uninfected controls (Hedges’ g 2.00 [95%CI 1.05, 2.94]; z = 4.12, p < 0.0001). These remained elevated despite successful ART (Hedges’ g 2.05 [95%CI 0.58, 3.52]; z = 2.71, p = 0.0067).ConclusionThe levels of platelet activation are elevated in treatment-naïve HIV-infected patients, and these persist during successful ART. Further studies should assess the clinical relevance of monitoring the levels of platelet activation in HIV-infected patients on ART.

Plasma Extracellular Vesicle Subtypes as Potential Biomarkers of Immune Activation in HIV-Infected Patients

Chronic immune activation and systemic inflammation during HIV infection despite effective antiretroviral therapy (ART) is associate with non-AIDS co-morbidities in people living with HIV (PLWH). Previous studies have shown that plasma levels of extracellular vesicles (EVs) may be used as immune activation or inflammatory biomarkers of HIV disease progression. Several studies have focused on microRNA and mitochondrial DNA (mtDNA) levels reached concomitantly in immune cells and EVs. We hypothesized that large and small EVs could contain different amounts of microRNA and mtDNA and that could reflect immune activation associated with elevated CD8 T cell count or low CD4/CD8 ratio in PLWH receiving ART. Plasma EVs obtained from PLWH and uninfected control were sized using dynamic light scattering and quantified using flow cytometry. Expression of mature miR-92, miR-155, miR-223 and mtDNA was measured by qRT-PCR. Positive correlation have been observed between CD8+ T cell count and large EV abundance, AChE activity in small EVs and negative correlation with miR-155 levels in small EVs. CD4/CD8 ratio was positively correlated with large EVs abundance and negatively with AChE activity in small EVs and PMN-associated copies of miR-92. MicroRNA-155 level in small EVs were positively correlated with monocyte counts. MiR-155 and mtDNA contents of large EVs were increased more than miR-92 and miR-223 contents in small EVs. A positive correlation was observed between large EVs mtDNA content and CD4 T cell count. These findings suggest that profiling the microRNA and mtDNA contents of EV might provide new functional biomarkers of immune activation and inflammation. Funding Statement: This study was funded through Canadian Institutes of Health Research (CIHR) grants MOP 188726; MOP-267056 (HIV/AIDS initiative) to C.G., MOP-03230 to J.P.R. and to C.T. for the cohort establishment and CIHR Foundation Grant FDN-143218 to M.A. for the studentship awarded to W.W.B., as well as by the Fonds de recherche du Quebec – Sante (FRQ-S) AIDS and infectious diseases network. C.T. is an FRQ-S scholar and holder of the Pfizer/Universite de Montreal chair on HIV translational Research. J-P.R. holds the Louis Lowenstein chair in Hematology & Oncology at McGill University. M-A.J. holds a CIHR Canada Research Chair tier 2 in Immuno-Virology. The infrastructure of the Centre de recherche du CHU de Quebec – Universite Laval is supportes by the FRQ-S. Declaration of Interests: The authors declare that no competing interests exist. Ethics Approval Statement: This study received approval from the ethics review boards of Centre de recherche du CHU de Quebec, Quebec, Canada and the McGill University Health Centre, Montreal, Quebec, Canada. All subjects were anonymous volunteers and provided written informed consent to participate in the study.

Motor-related brain abnormalities in HIV-infected patients: a multimodal MRI study.

It is generally believed that HIV infection could cause HIV-associated neurocognitive disorders (HAND) across a broad range of functional domains. Some of the most common findings are deficits in motor control. However, to date no neuroimaging studies have evaluated basic motor control in HIV-infected patients using a multimodal approach. In this study, we utilized high-resolution structural imaging and task-state functional magnetic resonance imaging (fMRI) to assess brain structure and motor function in a homogeneous cohort of HIV-infected patients. We found that HIV-infected patients had significantly reduced gray matter (GM) volume in cortical regions, which are involved in motor control, including the bilateral posterior insula cortex, premotor cortex, and supramarginal gyrus. Increased activation in bilateral posterior insula cortices was also demonstrated by patients during hand movement tasks compared with healthy controls. More importantly, the reduced GM in bilateral posterior insula cortices was spatially coincident with abnormal brain activation in HIV-infected patients. In addition, the results of partial correlation analysis indicated that GM reduction in bilateral posterior insula cortices and premotor cortices was significantly correlated with immune system deterioration. This study is the first to demonstrate spatially coincident GM reduction and abnormal activation during motor performance in HIV-infected patients. Although it remains unknown whether the brain deficits can be recovered, our findings may yield new insights into neurologic injury underlying motor dysfunction in HAND.

Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

Distribution and Activation of CD8+ T Cells in the Duodenal Mucosa before and after HIV Seroconversion.

CD8+ T cells in the intestinal mucosa influence the HIV-associated pathogenesis, but little is known about the dynamics of mucosal CD8+ T cell counts and activation of these cells during the course of infection. In this study, mucosal CD8+ T cells in the duodenum were studied at different stages of HIV infection, starting from the seronegative phase. In seronegative acute HIV infection, CD8+ T cell counts increased in the epithelium, but not in the lamina propria. Infiltration of the lamina propria by peripherally expanded CD8+ T cells was observed after seroconversion. Highest increase in the expression of perforin, the rate-limiting molecule for cytotoxic CD8+ T cell activity, was evident in the lamina propria of seronegative acutely HIV-infected patients. The number of perforin-expressing cells in the lamina propria of acutely HIV-infected patients was positively associated with biomarkers of enterocyte damage and microbial translocation. After seroconversion, perforin expression was downregulated in the lamina propria, but not in the epithelium. In conclusion, our findings demonstrate that intraepithelial and lamina propria CD8+ T cells exhibit different dynamics of numerical alteration and cytotoxic activity in HIV-infected patients. Moreover, our results suggest that perforin-dependent cytotoxic mechanisms by CD8+ T cells could impair the intestinal mucosal barrier already in the seronegative phase of acute HIV infection, thereby inducing microbial translocation as one of the earliest pathological events in HIV infection.

Protective Effect of Diosgenin against H2O2-Induced Oxidative Stress on H9C2 Cells

Diosgenin is an important compound in pharmaceutical industry. It has various effects such as hypocholesterolemic action or antioxidant activity in HIV infected patients. Biological oxidation pathways are involved in causing or aggravating heart disease. This study investigated the potential protective effect of diosgenin on cell viability and antioxidant defenses of cultured H9C2 cells submitted to oxidative stress induced by H2O2. Viability of cells exposed to H2O2 was detected by MTT assay. The generation of ROS and hydrogen peroxide release after H2O2 were detected using the fluorescent probe H2DCF-DA. The lipid peroxidation product i.e. MDA formation was estimated by assessing the levels of thio-barbituric acid reactive substances (TBARS) using spectrophotometry. SOD activity was assayed with NWLSS (TM) Superoxide Dismutase (SOD) activity assay kit. Pretreatment of cells with 3-25 µM of diosgenin for 24 h before applying H2O2 completely prevented cell damage and significantly enhanced viability of H9C2 cells. Increased ROS induced by H2O2 was dose dependently prevented when cells were pretreated for 24 h with diosgenin. The level of the lipid peroxidation was significantly higher in H9C2 cells exposed to H2O2 as compared to the control and cells pretreated with diosgenin. SOD activity in cells treated with diosgenin significantly decreased compared with cells exposed to H2O2. These results show that treatment of H9C2 cells with diosgenin (3-25 µM) confers a significant protection against oxidative stress.

Causes of T lymphocyte activation in HIV-infected patients coinfected with hepatitis C virus

To establish the causes of T lymphocyte activation in human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis C (HCV) who are adherent to their antiretroviral therapy regimen and interferon untreated. Examinations were made in 62 people who were HIV+HCV-positive (n=21), HIV+HCV-negative (n=21), and noninfected volunteers (n=20). The activation (CD38+HLA-DR+) and proliferation (Ki-67+) of CD4+ and CD8+ T lymphocytes were estimated. The blood concentration of intestinal fatty acid-binding protein (I-FABP) was determined. The proportion of activated cells among the CD4+ T lymphocytes was equal in the HIV+HCV-positive and HIV+HCV-negative groups. But these indicators were statistically significantly higher than those in the controls (HIV- HCV-). CD8+ T cell activation was greater in the HIV/HCV-coinfected patients than that in the other groups and that was higher in the HIV monoinfected than in the noninfected. The blood I-FABP concentrations were elevated in the HIV+HCV-positive and HIV+HCV groups compared with those in the HIV-HCV-negative group, but these did not differ among themselves. In the HIV+HCV-negative patients, CD4+ and CD8+ T cell activation directly and statistically significantly correlated with blood I-FABP levels. In the HIV+HCV-positive group, this correlation remained only for CD4+ T lymphocytes. CD8+ T cell activation in HIV/HCV-coinfected patients was unrelated to I-FABP concentrations. The increased activation of CD4+ and CD8+ T lymphocytes in HIV monoinfection was found to be associated with intestinal epithelial destruction and unrelated to cell division processes. In HIV/HCV coinfection, the activated state of CD4+ T cells is determined by both the level of proliferative processes and impairment of the intestinal barrier and that of CD8+ T cells is only by proliferation.

Mechanisms by Which Interleukin-12 Corrects Defective NK Cell Anticryptococcal Activity in HIV-Infected Patients.

ABSTRACTCryptococcus neoformans is a pathogenic yeast and a leading cause of life-threatening meningitis in AIDS patients. Natural killer (NK) cells are important immune effector cells that directly recognize and kill C. neoformans via a perforin-dependent cytotoxic mechanism. We previously showed that NK cells from HIV-infected patients have aberrant anticryptococcal killing and that interleukin-12 (IL-12) restores the activity at least partially through restoration of NKp30. However, the mechanisms causing this defect or how IL-12 restores the function was unknown. By examining the sequential steps in NK cell killing of Cryptococcus, we found that NK cells from HIV-infected patients had defective binding of NK cells to C. neoformans. Moreover, those NK cells that bound to C. neoformans failed to polarize perforin-containing granules to the microbial synapse compared to healthy controls, suggesting that binding was insufficient to restore a defect in perforin polarization. We also identified lower expression of intracellular perforin and defective perforin release from NK cells of HIV-infected patients in response to C. neoformans. Importantly, treatment of NK cells from HIV-infected patients with IL-12 reversed the multiple defects in binding, granule polarization, perforin content, and perforin release and restored anticryptococcal activity. Thus, there are multiple defects in the cytolytic machinery of NK cells from HIV-infected patients, which cumulatively result in defective NK cell anticryptococcal activity, and each of these defects can be reversed with IL-12.

Short Communication: Immune Activation Is Present in HIV-1-Exposed Seronegative Individuals and Is Independent of Microbial Translocation.

Analyses of immune activation in HIV-exposed seronegative individuals (HESN) yielded discrepant results. To clarify this issue we performed an extensive investigation of immune parameters in HESN and, in particular, we analyzed in these individuals the possible presence of microbial translocation, the most widely accepted reason driving immune activation in HIV-infected patients. Results showed that immune activation, a skewing of T lymphocyte maturation, and increased responsiveness to lipopolysaccharide (LPS) characterize the HESN phenotype; this is not driven by alterations of the gastrointestinal barrier and microbial translocation. The activation state seen in HESN may influence the induction of stronger adaptive antiviral immune responses and may represent a virus exposure-induced innate immune protective phenotype against HIV.

Differential effects of viremia and microbial translocation on immune activation in HIV-infected patients throughout ritonavir-boosted darunavir monotherapy.

The purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4+ and CD8+ T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv).Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4+ and CD8+ T cells, and plasma sCD14 levels.Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4+ (ρ = −0.352, P = 0.01) and CD8+ T-cell activation (ρ = −0.468, P < 0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4 pg/mL; P < 0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4+ and CD8+ T cells activation was an undetectable HIV-1 viremia (β = 4.78, P < 0.001 and β = 2.93, P = 0.005, respectively).MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4+ and CD8+ T-cells IA, even during mtDRV/rtv.

Soluble CD40-ligand (sCD40L, sCD154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection.

CD40/CD40-ligand (CD40L) signalling is a key stimulatory pathway which triggers the tryptophan (Trp) catabolizing enzyme IDO in dendritic cells and is immunosuppressive in cancer. We reported IDO-induced Trp catabolism results in a T helper type 17 (Th17)/regulatory T cell (Treg ) imbalance, and favours microbial translocation in HIV chronic infection. Here we assessed the link between sCD40L, Tregs and IDO activity in HIV-infected patients with different clinical outcomes. Plasmatic sCD40L and inflammatory cytokines were assessed in anti-retroviral therapy (ART)-naive, ART-successfully treated (ST), elite controllers (EC) and healthy subjects (HS). Plasma levels of Trp and its metabolite Kynurenine (Kyn) were measured by isotope dilution tandem mass spectrometry and sCD14 was assessed by enzyme-linked immunosorbent assay (ELISA). IDO-mRNA expression was quantified by reverse transcription-polymerase chain reaction (RT-PCR). The in-vitro functional assay of sCD40L on Treg induction and T cell activation were assessed on peripheral blood mononuclear cells (PBMCs) from HS. sCD40L levels in ART-naive subjects were significantly higher compared to ST and HS, whereas EC showed only a minor increase. In ART-naive alone, sCD40L was correlated with T cell activation, IDO-mRNA expression and CD4 T cell depletion but not with viral load. sCD40L was correlated positively with IDO enzymatic activity (Kyn/Trp ratio), Treg frequency, plasma sCD14 and inflammatory soluble factors in all HIV-infected patients. In-vitro functional sCD40L stimulation induced Treg expansion and favoured Treg differentiation by reducing central memory and increasing terminal effector Treg proportion. sCD40L also increased T cell activation measured by co-expression of CD38/human leucocyte antigen D-related (HLA-DR). These results indicate that elevated sCD40L induces immunosuppression in HIV infection by mediating IDO-induced Trp catabolism and Treg expansion.

Reduced sTWEAK and Increased sCD163 Levels in HIV-Infected Patients: Modulation by Antiretroviral Treatment, HIV Replication and HCV Co-Infection

BackgroundPatients infected with the human immunodeficiency virus (HIV) have an increased risk of cardiovascular disease due to increased inflammation and persistent immune activation. CD163 is a macrophage scavenger receptor that is involved in monocyte-macrophage activation in HIV-infected patients. CD163 interacts with TWEAK, a member of the TNF superfamily. Circulating levels of sTWEAK and sCD163 have been previously associated with cardiovascular disease, but no previous studies have fully analyzed their association with HIV.ObjectiveThe aim of this study was to analyze circulating levels of sTWEAK and sCD163 as well as other known markers of inflammation (hsCRP, IL-6 and sTNFRII) and endothelial dysfunction (sVCAM-1 and ADMA) in 26 patients with HIV before and after 48 weeks of antiretroviral treatment (ART) and 23 healthy subjects.ResultsPatients with HIV had reduced sTWEAK levels and increased sCD163, sVCAM-1, ADMA, hsCRP, IL-6 and sTNFRII plasma concentrations, as well as increased sCD163/sTWEAK ratio, compared with healthy subjects. Antiretroviral treatment significantly reduced the concentrations of sCD163, sVCAM-1, hsCRP and sTNFRII, although they remained elevated when compared with healthy subjects. Antiretroviral treatment had no effect on the concentrations of ADMA and sTWEAK, biomarkers associated with endothelial function. The use of protease inhibitors as part of antiretroviral therapy and the presence of HCV-HIV co-infection and/or active HIV replication attenuated the ART-mediated decrease in sCD163 plasma concentrations.ConclusionHIV-infected patients showed a proatherogenic profile characterized by increased inflammatory, immune-activation and endothelial-dysfunction biomarkers that partially improved after ART. HCV-HIV co-infection and/or active HIV replication enhanced immune activation despite ART.

Impact of Autologous Dendritic Cell–Based Immunotherapy (AGS-004) on B- and T-Cell Subset Changes and Immune Activation in HIV-Infected Patients Receiving Antiretroviral Therapy

We previously reported that a combination of antiretroviral therapy with 4 monthly injections of each patient's own autologous dendritic cells (AGS-004) electroporated with CD40 ligand and with HIV RNA antigens obtained from each patient's own pre-antiretroviral therapy plasma induced HIV-specific CD8 T-cell responses in 10 patients. To assess other AGS-004-induced immune changes, we evaluated the modifications in B- and T-cell subsets and the level of immune activation in these patients. The proportion of Bm1 naive cells was increased along with an augmentation of the proliferation marker Ki67. Memory B-cell frequency, CD4 and CD8 T-cell subsets, regulatory T-cell frequency, and CD38/HLA-DR/PD-1 T-cell activation levels remained unchanged after AGS-004 dendritic cell immunotherapy.

The HIV-1 Tat Protein Induces the Activation of CD8+ T Cells and Affects In Vivo the Magnitude and Kinetics of Antiviral Responses

T cells are functionally compromised during HIV infection despite their increased activation and proliferation. Although T cell hyperactivation is one of the best predictive markers for disease progression, its causes are poorly understood. Anti-tat natural immunity as well as anti-tat antibodies induced by Tat immunization protect from progression to AIDS and reverse signs of immune activation in HIV-infected patients suggesting a role of Tat in T cell dysfunctionality. The Tat protein of HIV-1 is known to induce, in vitro, the activation of CD4+ T lymphocytes, but its role on CD8+ T cells and how these effects modulate, in vivo, the immune response to pathogens are not known. To characterize the role of Tat in T cell hyperactivation and dysfunction, we examined the effect of Tat on CD8+ T cell responses and antiviral immunity in different ex vivo and in vivo models of antigenic stimulation, including HSV infection. We demonstrate for the first time that the presence of Tat during priming of CD8+ T cells favors the activation of antigen-specific CTLs. Effector CD8+ T cells generated in the presence of Tat undergo an enhanced and prolonged expansion that turns to a partial dysfunctionality at the peak of the response, and worsens HSV acute infection. Moreover, Tat favors the development of effector memory CD8+ T cells and a transient loss of B cells, two hallmarks of the chronic immune activation observed in HIV-infected patients. Our data provide evidence that Tat affects CD8+ T cell responses to co-pathogens and suggest that Tat may contribute to the CD8+ T cell hyperactivation observed in HIV-infected individuals.

GB virus C infection and B-cell, natural killer cell, and monocyte activation markers in HIV-infected individuals

GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16- natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T-cell immune activation in individuals with HIV infection.

Abnormal MEG Oscillatory Activity during Visual Processing in the Prefrontal Cortices and Frontal Eye-Fields of the Aging HIV Brain

ObjectiveShortly after infection, HIV enters the brain and causes widespread inflammation and neuronal damage, which ultimately leads to neuropsychological impairments. Despite a large body of neuroscience and imaging studies, the pathophysiology of these HIV-associated neurocognitive disorders (HAND) remains unresolved. Previous neuroimaging studies have shown greater activation in HIV-infected patients during strenuous tasks in frontal and parietal cortices, and less activation in the primary sensory cortices during rest and sensory stimulation.MethodsHigh-density magnetoencephalography (MEG) was utilized to evaluate the basic neurophysiology underlying attentive, visual processing in older HIV-infected adults and a matched non-infected control group. Unlike other neuroimaging methods, MEG is a direct measure of neural activity that is not tied to brain metabolism or hemodynamic responses. During MEG, participants fixated on a centrally-presented crosshair while intermittent visual stimulation appeared in their top-right visual-field quadrant. All MEG data was imaged in the time-frequency domain using beamforming.ResultsUninfected controls had increased neuronal synchronization in the 6–12 Hz range within the right dorsolateral prefrontal cortex, right frontal eye-fields, and the posterior cingulate. Conversely, HIV-infected patients exhibited decreased synchrony in these same neural regions, and the magnitude of these decreases was correlated with neuropsychological performance in several cortical association regions.ConclusionsMEG-based imaging holds potential as a noninvasive biomarker for HIV-related neuronal dysfunction, and may help identify patients who have or may develop HAND. Reduced synchronization of neural populations in the association cortices was strongly linked to cognitive dysfunction, and likely reflects the impact of HIV on neuronal and neuropsychological health.

Abnormal MEG oscillatory activity during visual processing in the prefrontal cortices and frontal eye-fields of the aging HIV brain.

Shortly after infection, HIV enters the brain and causes widespread inflammation and neuronal damage, which ultimately leads to neuropsychological impairments. Despite a large body of neuroscience and imaging studies, the pathophysiology of these HIV-associated neurocognitive disorders (HAND) remains unresolved. Previous neuroimaging studies have shown greater activation in HIV-infected patients during strenuous tasks in frontal and parietal cortices, and less activation in the primary sensory cortices during rest and sensory stimulation. High-density magnetoencephalography (MEG) was utilized to evaluate the basic neurophysiology underlying attentive, visual processing in older HIV-infected adults and a matched non-infected control group. Unlike other neuroimaging methods, MEG is a direct measure of neural activity that is not tied to brain metabolism or hemodynamic responses. During MEG, participants fixated on a centrally-presented crosshair while intermittent visual stimulation appeared in their top-right visual-field quadrant. All MEG data was imaged in the time-frequency domain using beamforming. Uninfected controls had increased neuronal synchronization in the 6-12 Hz range within the right dorsolateral prefrontal cortex, right frontal eye-fields, and the posterior cingulate. Conversely, HIV-infected patients exhibited decreased synchrony in these same neural regions, and the magnitude of these decreases was correlated with neuropsychological performance in several cortical association regions. MEG-based imaging holds potential as a noninvasive biomarker for HIV-related neuronal dysfunction, and may help identify patients who have or may develop HAND. Reduced synchronization of neural populations in the association cortices was strongly linked to cognitive dysfunction, and likely reflects the impact of HIV on neuronal and neuropsychological health.