The latest medical research on Immunology & Allergy
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Request AccessAssociation between tight junction proteins and cognitive performance in untreated Persons living with HIV (PLWH).
AIDSHIV-associated neurocognitive disorders (HAND) still affects persons living with HIV (PLWH) and their pathogenesis isn't completely understood. We aimed to explore the association between plasma and CSF markers of blood-brain barrier (BBB) impairment and HAND in untreated PLWH.
We enrolled untreated PLWH, who underwent blood exams and lumbar puncture to measure inflammation (IL-15, TNF-α), BBB damage (zonulin and tight junction proteins, TJs: occludin, claudin-5) and endothelial adhesion molecules (VCAM-1, ICAM-1). A comprehensive neurocognitive battery was used to diagnose HAND (Frascati criteria).
Twenty-one patients (21/78, 26,9%) patients presented HAND (100% ANI). HAND patients displayed more frequently non-CNS AIDS-defining conditions, lower nadir CD4+ T-cells and increased CD4+ T-cell exhaustion (lower CD4+CD127+ and CD4+CD45RA+ T cells percentages), in comparison to subjects without cognitive impairment. Furthermore, HAND was characterized by higher plasma inflammation (IL-15), but lower CSF levels of biomarkers of BBB impairment (zonulin and occludin). The association between BBB damage with HAND was confirmed by fitting a multivariable logistic regression. CSF/plasma endothelial adhesion molecules weren't associated with HAND, but with a poor performance in different cognitive domains.
By showing heightened inflammation and BBB impairment, our study suggests loss of BBB integrity as a possible factor contributing to the development of HAND in untreated PLWH.
Paclitaxel Inhibits Proliferation by Negatively Regulating Cdk1-Cell Cycle Axis in Rat Airway Smooth Muscle Cells.
J AsthmaPaclitaxel exhibits outstanding biological activities in inhibiting cell proliferation and inducing cell apoptosis. But the effects of paclitaxel on airway smooth muscle cells (ASMCs) have not been reported yet. The purpose of this study is to determine the effects of paclitaxel on the proliferation and apoptosis of ASMCs.
Rat primary ASMCs were isolated and used in all the experiments. Cell Counting Kit-8 (CCK-8) assay and Edu assay were used to analyse the cell viability and proliferation respectively. Flow cytometry was used to detect the cell cycle and apoptosis. Quantitative real-time PCR (qRT-PCR), western blotting, and immunostaining were used to detect the expression of Cyclin-dependent kinase 1 (Cdk1).
Our study showed that paclitaxel inhibits the proliferation of ASMCs in a dose and time gradient dependent manner. Further study displayed that cell cycle is arrested at G2/M phase. And Cdk1 was dramatically down-regulated by paclitaxel treatment. Cell morphological analysis showed that ASMCs are elliptical with a larger surface area after paclitaxel treatment. Nucleus morphological analysis showed that the nuclei are in a diffuse state after paclitaxel treatment. But paclitaxel did not induce the apoptosis of ASMCs.
Our study demonstrated that paclitaxel inhibits the proliferation of ASMCs at least partly by negatively regulating Cdk1-cell cycle axis.
Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission.
Current Opinion in Cell BiologySuccessful sustained remission of HIV infection has been achieved after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation for treatment of leukemia in a small cohort of people living with HIV (PLWH). This breakthrough demonstrated that the goal of curing HIV was achievable. However, the high morbidity and mortality associated with bone marrow transplantation limits the routine application of this approach and provides a strong rationale for pursuing alternative strategies for sustained long-term antiretroviral therapy (ART)-free HIV remission. Notably, long-term immune-mediated control of HIV replication observed in elite controllers and posttreatment controllers suggests that potent HIV-specific immune responses could provide sustained ART-free remission in PLWH. The capacity of chimeric antigen receptor (CAR)-T cells engineered to target malignant cells to induce remission and cure in cancer patients made this an attractive approach to provide PLWH with a potent HIV-specific immune response. Here, we review the recent advances in the design and application of anti-HIV CAR-T-cell therapy to provide a functional HIV cure.
HIV reservoirs are established days after infection and persist through clonal expansion of infected cells. The continuous interaction between latently infected cells and the immune system shapes the landscape of HIV latency and likely contributes to ART-free viral control in elite controllers. CAR-T cells can exhibit superior antiviral activity as compared with native HIV-specific T cells, particularly because they can be engineered to have multiple HIV specificities, resistance to HIV infection, dual costimulatory signaling, immune checkpoint inhibitors, stem cell derivation, CMV TCR coexpression, and tissue homing ligands. These modifications can significantly improve the capacities of anti-HIV CAR-T cells to prevent viral escape, resist HIV infection, and enhance cytotoxicity, persistence, and tissue penetration. Collectively, these novel modifications of anti-HIV CAR-T cell design have increased their capacity to control HIV infection.
Anti-HIV CAR-T cells can be engineered to provide potent and sustained in-vitro and in-vivo antiviral function. The combination of anti-HIV CAR-T cells with other immunotherapeutics may contribute to long-term HIV remission in PLWH.
Distinct anal microbiome is correlated with anal cancer precursors in men who have sex with men living with HIV.
AIDSAnal cancer risk is elevated in men who have sex with men living with HIV (MSMLWH). Anal high-risk human papillomavirus (hr-HPV) infection is necessary but insufficient to develop high-grade squamous intraepithelial lesion (HSIL), the anal cancer precursor, suggesting additional factors. We sought to determine whether the microbiome of the anal canal is distinct by comparing it with the microbiome of stool. We also sought to determine whether changes in the anal microbiome are associated with HSIL among MSMLWH.
Sterile swabs were used to sample the anus of MSMLWH for microbiome and HPV testing, followed by high-resolution anoscopy. Stool samples were mailed from home. 16S sequencing was used for bacterial identification. Measures of alpha diversity, beta diversity and differential abundance analysis were used to compare samples.
166 anal samples and 103 matching stool samples were sequenced. Beta diversity showed clustering of stool and anal samples. Of hr-HPV-positive MSMLWH, 31 had HSIL and 13 had no SIL. Comparison of the microbiome between these revealed 28 different species. The highest-fold enrichment among MSMLWH/hr-HPV/HSIL included pro-inflammatory and carcinogenic Prevotella, Parasuterella, Hungatella, Sneathia and Fusobacterium species. The anti-inflammatory Anaerostipes caccae showed the greatest reduction among MSMLWH/hr-HPV/HSIL.
The anal microbiome is distinct from stool. A pro-inflammatory and carcinogenic environment may be associated with anal HSIL.
Risk score prediction for bacteriologically confirmed tuberculosis among HIV-infected adults on antiretroviral therapy in Ethiopia: prognostic model development.
AIDSThis study was aimed at developing a risk score prediction model for bacteriologically confirmed TB among HIV-infected adults receiving antiretroviral therapy in Ethiopia.
An institutional-based retrospective follow-up study was conducted among 569 HIV-infected adults on ART. We used demographic and clinical prognostic factors to develop a risk prediction model. Model performance was evaluated by discrimination and calibration using the area under the receiver operating characteristic (AUROC) curve and calibration plot. Bootstrapping was used for internal validation. A decision curve analysis was used to evaluate the clinical utility.
Opportunistic infection, functional status, anemia, isoniazid preventive therapy, and WHO clinical stages were used to develop risk prediction. The AUROC curve of the original model was 87.53% (95% CI: 83.88-91.25) and the calibration plot (p-value = 0.51). After internal validation, the AUROC curve of 86.61% (95% CI: 82.92-90.29%) was comparable with the original model, with an optimism coefficient of 0.0096 and good calibration (p-value = 0.10). Our model revealed excellent sensitivity (92.65%) and negative predictive value (NPV) (98.60%) with very good specificity (70.06%) and accuracy (72.76%). After validation, accuracy (74.85%) and specificity (76.27%) were improved, but sensitivity (86.76%) and NPV (97.66%) were relatively reduced. The risk prediction model had a net benefit up to 7.5 threshold probabilities.
This prognostic model had very good performance. Moreover, it had very good sensitivity and excellent NPV. The model could help clinicians use risk estimation and stratification for early diagnosis and treatment to improve patient outcomes and quality of life.
The health equity implications of the Health Resources and Services Administration's Ryan White HIV/AIDS Program.
AIDSInvestigate the role of the Ryan White HIV/AIDS Program (RWHAP) - which funds services for vulnerable and historically disadvantaged populations with HIV - in reducing health inequities among people with HIV over a 10-year horizon.
We use a composite measure (the Theil index) to evaluate the health equity implications of the RWHAP for each of four subgroups (based on race and ethnicity, age, gender, and HIV transmission category) and two outcomes (probability of being in care and treatment and probability of being virally suppressed). We compare results with the RWHAP fully funded versus a counterfactual scenario, in which the medical and support services funded by the RWHAP are not available.
The model indicates the RWHAP will improve health equity across all demographic subgroups and outcomes over a 10-year horizon. In Year 10, the Theil index for race and ethnicity is 99% lower for both outcomes under the RWHAP compared to the non-RWHAP scenario; 71-93% lower across HIV transmission categories; 31-44% lower for age; and 73-75% lower for gender.
Given the large number of people served by the RWHAP and our findings on its impact on equity, the RWHAP represents an important vehicle for achieving the health equity goals of the National HIV/AIDS Strategy (2022-2025) and the Ending the HIV Epidemic Initiative goal of reducing new infections by 90% by 2030.
Progress towards achieving national goals for improved quality of life among cis-gender Black women with HIV.
AIDSData from the CDC's Medical Monitoring Project indicate that the United States is on track to meet one of five National HIV/AIDS Strategy (NHAS) Qu...
Proteomics discovery in children and young adults with HIV identifies fibrosis, inflammatory, and immune biomarkers associated with myocardial impairment.
AIDSPeople with HIV are at increased risk of cardiac dysfunction; however, limited tools are available to identify patients at highest risk for future ...
A behavioral economics approach to enhancing HIV preexposure and postexposure prophylaxis implementation.
Current Opinion in Cell BiologyThe 'PrEP cliff' phenomenon poses a critical challenge in global HIV PrEP implementation, marked by significant dropouts across the entire PrEP care continuum. This article reviews new strategies to address 'PrEP cliff'.
Canadian clinicians have developed a service delivery model that offers presumptive PEP to patients in need and transits eligible PEP users to PrEP. Early findings are promising. This service model not only establishes a safety net for those who were not protected by PrEP, but it also leverages the immediate salience and perceived benefits of PEP as a natural nudge towards PrEP use. Aligning with Behavioral Economics, specifically the Salience Theory, this strategy holds potential in tackling PrEP implementation challenges.
A natural pathway between PEP and PrEP has been widely observed. The Canadian service model exemplifies an innovative strategy that leverages this organic pathway and enhances the utility of both PEP and PrEP services. We offer theoretical insights into the reasons behind these PEP-PrEP transitions and evolve the Canadian model into a cohesive framework for implementation.
Gaining momentum: stem cell therapies for HIV cure.
Current Opinion in Cell BiologyDurable HIV-1 remission has been reported in a person who received allogeneic stem cell transplants (SCTs) involving CCR5 Δ32/Δ32 donor cells. Much of the reduction in HIV-1 burden following allogeneic SCT with or without donor cells inherently resistant to HIV-1 infection is likely due to cytotoxic graft-versus-host effects on residual recipient immune cells. Nonetheless, there has been growing momentum to develop and implement stem cell therapies that lead to durable long-term antiretroviral therapy (ART)-free remission without the need for SCT.
Most current research leverages gene editing techniques to modify hematopoietic stem cells which differentiate into immune cells capable of harboring HIV-1. Approaches include targeting genes that encode HIV-1 co-receptors using Zinc Finger Nucleases (ZFN) or CRISPR-Cas-9 to render a pool of adult or progenitor cells resistant to de-novo infection. Other strategies involve harnessing multipotent mesenchymal stromal cells to foster immune environments that can more efficiently recognize and target HIV-1 while promoting tissue homeostasis.
Many of these strategies are currently in a state of infancy or adolescence; nonetheless, promising preclinical and first-in-human studies have been performed, providing further rationale to focus resources on stem cell therapies.
Utilizing immunotherapy towards achieving a functional cure for HIV-1.
Current Opinion in Cell BiologyAdvancements in antiretroviral therapy (ART) have positively impacted the life expectancy and possibility of living a normal life for people with HIV-1. However, lifelong daily medication is necessary to prevent disease progression. To this end, immunotherapeutic strategies are being tested with the aim of developing a functional cure in which the immune system effectively controls HIV-1 in the absence of ART.
The most promising advances in achieving sustained HIV-1 remission or cure include broadly neutralizing antibodies (bNAbs) that are administered alone or in combination with other agents. Newer and more innovative approaches redirecting T cells or natural killer cells to kill HIV-1 infected cells have also shown promising results. Finally, multiple ongoing trials focus on combining bNAbs with other immune-directed therapies to enhance both innate and adaptive immunity.
While immunotherapies as an alternative to conventional ART have generally proven to be well tolerated, these therapeutic approaches have largely been unsuccessful in inducing ART-free control of HIV-1. However, promising results from recent trials involving bNAbs that have reported durable HIV-1 control among a subset of participants, provide reason for cautious optimism that we with further optimization of these treatment strategies may be able to achieve functional cure for HIV-1.
Nebulizers.
Journal of Aerosol Medicine andNebulizers generate aerosols from liquid-based solutions and suspensions. Nebulizers are particularly well suited to delivering larger doses of med...
