Can statin preventative treatment inform geroscience-guided therapeutics?

: Potential senotherapeutic effect of statins may lead to prevention and reduction of frailty

VACUTAINER(® )CPT™ and Ficoll density gradient separation perform equivalently in maintaining the quality and function of PBMC from HIV seropositive blood samples

BACKGROUND: For immune monitoring studies during HIV vaccine clinical trials, whole blood specimens from HIV seropositive (HIV(+)) patients may be collected at multiple sites and sent to a central location for peripheral blood mononuclear cell (PBMC) isolation, cryopreservation and functional evaluation. In this study we show a comparison of two PBMC preparation options, Ficoll density gradient separation (Ficoll) and Cell Preparation Tubes (CPT) using shipped whole blood specimens from 19 HIV(+ )patients (CD4 > 350, viral load < 50). The pre- and post- cryopreservation performance of samples collected by these two methods were compared by assessment of antigen-specific IFNγ expression in CD8(+ )and CD8(- )T cells, cellular viability, and cellular recovery. RESULTS: The results indicate that cryopreserved PBMC samples tested for CMV- and HIV- specific interferon-gamma (IFNγ) expression performed equivalent to the respective fresh PBMC processed under both collection conditions. Compared to fresh PBMC, the viability was significantly lower for cryopreserved PBMC derived using Ficoll, although it was never less than 90%. There were no significant differences in the IFNγ response, viability, or recovery between cryopreserved PBMC derived by Ficoll and by CPT. CONCLUSION: These data suggest that CPT is an efficient system for the collection and cryopreservation of functionally active HIV(+ )PBMC, as well as a viable alternative to Ficoll gradient separation

Increased CMV IgG Antibody Titer is Associated with Non-AIDS Events Among Virologically Suppressed HIV-Positive Persons

Background: Among HIV-positive individuals, increased levels of inflammation and immune activation persist even in the setting of effective antiretroviral therapy (ART) and are associated with greater rates of non-AIDS events. The etiology of this persistent inflammation is incompletely understood. Methods: Using a well-characterized cohort of 322 HIV-infected individuals on suppressive ART, we conducted a case-control study. Cytomegalovirus (CMV) immunoglobulin G (IgG) levels, plasma biomarkers, and T-cell phenotypes were measured/characterized from samples collected 1 year after ART initiation. Conditional logistic regression for matched case-control studies analyzed the associations of year 1 CMV-specific IgG level with the subsequent occurrence of any non-AIDS event. Correlations between continuous CMV IgG antibody levels and soluble and cellular markers were assessed. Results: We found that higher levels of CMV IgG were associated with increased risk of non-AIDS events (OR = 1.58 per IQR [95% CI: 1.12, 2.24], P = 0.01) and with elevated soluble and cellular markers of inflammation. Conclusions: The magnitude of the host immune response to CMV may play a role in the persistent inflammation and resultant morbid events observed in the HIV-positive population

Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women\u27s interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear. In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI). We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P \u3c 0.001, coefficient r = −0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV− except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV− groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA− (P = 0.005). HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals

Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1) formulated with the adjuvant IC31, was evaluated in HIV-infected adults. METHODS: HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay. RESULTS: 47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015). Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells. CONCLUSION: H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR) PACTR201105000289276

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study

Background: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID./ Objective: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID./ Methods: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV−COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID− arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV−COVID− arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post–acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID− arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID− arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID− arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored./ Results: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV−COVID+, 78 (22.6%) HIV+COVID−, and 70 (20.3%) HIV−COVID− participants./ Conclusions: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID

Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis

Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis

The relation of plasmacytoid dendritic cells (pDCs) and regulatory t-cells (Tregs) with HPV persistence in HIV-Infected and HIV-Uninfected women

Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted

A matched cross-sectional study of the association between circulating tissue factor activity, immune activation and advanced liver fibrosis in hepatitis C infection

Abstract Background 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. Methods 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. Results 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). Conclusions 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

T-cell receptor gene rearrangement and expression in human natural killer cells: natural killer activity is not dependent on the rearrangement and expression of T-cell receptor α , β , or γ genes

To test the hypothesis that the T-cell receptor ( Tcr ) λ gene encodes a natural killer (NK) cell receptor molecule, three human NK clones and fresh peripheral blood lymphocytes with NK activity from two patients with a CD16 + lymphocytosis were analyzed for rearrangements and expression of the human Tcr α, β , and λ genes. Two of the clones displayed distinct rearrangements of their Tcr β and λ genes and expressed mature Tcr α, β , and αl RNA. However, one of the clones and both patient samples displayed marked NK activity but failed to rearrange or express any of their Tcr genes. These findings demonstrate that human natural killer activity is not dependent on Tcr λ gene rearrangement and expression. In addition, they confirm previous findings concerning the lack of Tcr α and β gene expression in some natural killer cells. Thus, they suggest the existence of additional NK-specific recognition molecules.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46745/1/251_2004_Article_BF00376117.pd