Effective Antiretroviral Therapy Research Articles

Hepatic Flare Following Effective Antiretroviral Therapy Is Associated With HBsAg Seroclearance in HBV/HIV-1 Co-Infection.

Little is known about the clinical significance of hepatic flare following effective antiretroviral therapy (ART) on HBsAg seroclearance and prognosis in HBV/HIV co-infection. This observational cohort study recruited HBV/HIV-1 co-infected patients from the China National Free Antiretroviral Treatment Program. We obtained longitudinal information on demographic characteristics, clinical indicators, and treatment outcomes. Hepatic flare was defined as an elevation of ALT of more than five times the upper limit of the normal range without an upsurge of HBV DNA or HBsAg at any time point between ART initiation and 12 months. Among the 1354 enrolled patients, 98.7% received two anti-HBV drugs containing ART and 95.1% achieved good viral control. Hepatic flare was observed in 88 (6.5%) patients and was more frequent in those with lower baseline immune function but subsequently enhanced immune reconstitution. Over a median follow-up of 4.7 years, we observed 99 HBsAg seroclearance, 9 hepatic events, 6 HIV-associated malignancy, 3 non-HIV-associated malignancy, and 3 all-cause mortality. The 3-, 5-, and 10-year cumulative incidence of HBsAg seroclearance was 6.4%, 8.9%, and 12.9%, respectively. Compared to patients without hepatic flare, patients with hepatic flare had significantly higher rates of HBsAg seroclearance (13.6% vs. 6.9%, p = 0.018) but had no recorded adverse outcome. Multivariate analysis with different models indicated that hepatic flare was independently associated with HBsAg seroclearance especially in patients with low immune function, normal ALT, and high levels of HBV DNA and HBsAg at baseline. In HBV/HIV-1 co-infection, hepatic flare following effective ART is associated with HBsAg seroclearance. HBV-specific T cells immune reconstitution may represent a potential mechanism which deserves further investigation.

Non-pharmaceutical interventions for people living with HIV with cognitive impairment: A scoping review.

Cognitive impairment (CI) in HIV is often of multifactorial causation, and remains a prominent issue in the age of effective combination antiretroviral therapy (cART), affecting approximately 14% of people living with HIV. Despite the 2018 BHIVA directive stating the importance of commencing rehabilitation strategies in people living with HIV with CI, no types of cognitive rehabilitations or other non-pharmaceutical interventions are specifically recommended. This scoping review aimed to describe the types of and evidence relating to the non-pharmaceutical interventions which have been examined in people living with HIV with CI. Studies were identified from five electronic databases. Criteria for study inclusion were studies describing a non-pharmaceutical intervention published after 1st January 2000 in English, in a population of adults living with HIV with CI detected at baseline, without significant psychiatric or substance-misuse co-morbidity. Fourteen studies met the criteria for inclusion, with the Frascati criteria most commonly used to define CI within participant populations. The median intervention length was 12 weeks (IQR = 6.5). Nine studies investigated interventions with some component of computerised cognitive training (CCT); other interventions included diet, exercise and goal management training. Studies most commonly examined neurocognitive outcomes, but also considered other outcomes including quality of life, depressive symptomatology, intervention acceptability and cART adherence. Eight studies observed improvement in cognition with CCT, with effects often maintained for several weeks post-intervention, however, results were not always statistically significant. Self-reported cognitive improvement and intervention acceptability was high amongst participants completing CCT. There was heterogeneity across studies not only in intervention type, but in diagnostic tools used, the chosen outcome measures and cognitive batteries, making comparison difficult. Findings, however, indicate that CCT interventions may produce benefits in cognition and are acceptable to patients. Further research is required in larger samples, alongside identifying specific intervention components that improve outcomes.

Vitamin D and HIV: Description and correlation of serum levels with clinical and paraclinical variables

Introduction: Vitamin D (VD) has many extra-skeletal functions, such as immune regulation. It is important to recognize its role in patients infected by the human immunodeficiency virus (HIV). The objective of this study was to determine possible correlations between serum VD levels and multiple clinical and paraclinical variables in HIV-infected patients in the city of Bogotá, Colombia. Materials and methods: An observational, cross-sectional study was carried out on 161 HIV-infected patients in the city of Bogotá. VD levels were analyzed in relation to anthropometric classification of nutritional status, clinical and metabolic profile. Results: It was found a prevalence of low VD levels of 60.87%. Statistically significant correlations were detected between VD and the time of sun exposure reported by the patient and the type of antiretroviral therapy. In addition, using a linear regression model, it was found that the use of 2 nucleoside reverse transcriptase inhibitors + 1 integrase inhibitor correlates with hypovitaminosis, even with adequate time of sun exposure. No associations were found with age, sex, race, co morbidities, immune, or metabolic profile. Discussion: Although the pathophysiology of VD deficiency is multifactorial, low VD levels should be considered among the possible adverse effects of antiretro viral therapy and should be included in the usual follow-up of these patients.

Accelerated cognitive aging in chronically infected HIV-1 positive individuals despite effective long-term antiretroviral therapy.

People living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons.

Characterization of the Proinflammatory Cytokine Profile during Acute SARS-CoV-2 Infection in People with Human Immunodeficiency Virus.

Persistent inflammation during chronic human immunodeficiency virus (HIV) infection may affect the immune response against severe acute respiratory syndrome-coronavirus 2 (SARS- CoV-2) infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were measured in people with HIV (PWH) with effective combination antiretroviral therapy. There were no significant differences in any of the measured cytokines between severity levels of coronavirus disease 2019 (COVID-19) in PWH, while most were significantly higher in HIV-uninfected individuals with severe COVID-19, suggesting that excess cytokines release by hyperinflammatory responses do not occur in individuals with severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, particularly between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady-state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that they were in an enhanced inflammatory state. The absence of several inter-cytokine correlations was observed in in vitro lipopolysaccharide stimulus-driven cytokine production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially because of the underlying inflammatory state and/or impairment of innate immune cells.

Single-Cell Transcriptomics of Human Tonsils Reveals Nicotine Enhances HIV-1-Induced NLRP3 Inflammasome and Mitochondrial Activation.

HIV-1 infection, even with effective antiretroviral therapy (ART), is associated with chronic inflammation and immune dysfunction, contributing to long-term health complications. Nicotine use, prevalent among people with HIV (PWH), is known to exacerbate immune activation and disease progression, but the precise biological mechanisms remain to be fully understood. This study sought to uncover the synergistic effects of HIV-1 infection and nicotine on immune cell function, focusing on beneficial insights into NLRP3 inflammasome activation, oxidative stress, and mitochondrial pathways. Human tonsil explants were infected with HIV-1 and exposed to nicotine. Single-cell RNA sequencing was used to profile immune cell populations and gene expression linked to inflammasome activation, oxidative stress, and mitochondrial function. Gene set enrichment analysis (GSEA) and synergy assessments were conducted to investigate how nicotine modulates immune responses in the context of HIV. The combination of HIV infection and nicotine exposure significantly increased NLRP3 inflammasome activation, thioredoxin, and components of oxidative phosphorylation. This study highlights how the combined effects of HIV-1 and nicotine offer valuable insights into immune modulation, opening doors for future therapeutic strategies. Targeting the NLRP3 inflammasome and addressing nicotine use may contribute to improved outcomes for PWH.

Implementation of patient-reported outcomes for people living with HIV: Insights from patients and healthcare providers in a Danish outpatient clinic.

Patient-reported outcomes (PROs) have emerged as a valuable tool for aligning HIV care with patient needs and priorities. This study aimed to explore patient and healthcare provider (HCP) experiences of integrating a PRO solution into standard clinical care for HIV in a Danish outpatient clinic. A tailored PRO solution for people living with HIV was developed in a Danish outpatient clinic. Patients were eligible if they were aged >18 years, spoke Danish, had been on effective antiretroviral therapy for 2 years, and had no additional health issues. Patients completed an electronic questionnaire 14 days before in-clinic consultations. HCPs reviewed patients' responses before these consultations. We assessed the usability, acceptability, and relevance of the PRO solution by conducting semi-structured interviews with 24 patients (12 responders and 12 non-responders) and six HCPs. A further 95 non-responders were interviewed over the phone. Data were analysed using thematic analysis. Respondents found that PROs improved patient-provider communication, treatment planning, and self-management. Non-respondents faced barriers such as health literacy, cultural beliefs, and access to technology, necessitating alternative delivery methods. HCPs found that PROs facilitated person-centred care and symptom management, but HCPs faced challenges such as insufficient training, resources, and organizational support. Implementing PROs in HIV care is challenging because of the patient diversity, clinician training needs, and organizational adaptations. Nevertheless, the use of PROs is associated with enhanced person-centred care. Future recommendations include tailored use of PROs, better understanding of the impact on patient groups, on-site questionnaire completion, and emphasis on shared decision-making between patients and HCPs.

Abstract 4138220: Traditional and HIV-specific Risk Factors Are Associated with Incident Non-valvular Atrial Fibrillation and Atrial Flutter among Underrepresented Racial and Ethnic Minority Groups Living with HIV

Introduction: With effective antiretroviral therapy (ART), HIV can now be managed as a chronic disease. Chronic disease and cardiovascular risk factor management is especially important for underrepresented racial and ethnic minority groups (UREG). Non-valvular atrial fibrillation and atrial flutter (NVAF) have not been adequately studied in UREG with HIV. Research Questions: Among UREG with HIV, what is the incidence of NVAF? What factors are associated with incident NVAF? Aims: To narrow an evidence gap among UREG with HIV by 1) describing the incidence of NVAF and 2) identifying factors associated with incident NVAF. Methods: This is an ancillary study of the Pathways to Cardiovascular Disease Prevention and Impact of Specialty Referral in Underrepresented Racial and Ethnic Minorities with HIV (PATHWAYS) study, a retrospective population-based study of HIV care patterns among UREG with HIV. Patients without a known history of NVAF entered our study cohort at the date of their first documented HIV diagnosis. We computed the cumulative incidence of NVAF over five years of follow-up (mean 3.4, SD 1.6), handling death as a competing risk. Cox regression analysis was used to examine the univariate associations between characteristics at HIV diagnosis and incident NVAF, adjusting for site and date of HIV diagnosis. Results: From 2015-2019, 10,945 UREG meeting entry criteria were identified. On average, patients were 67.1% male, 94.4% Black, and 8.5% Hispanic. Average CHA2DS2VASc score was 0.92 (SD 1.1) and 63.4% were on ART. Cumulative incidence of NVAF at one and five years after HIV diagnosis were 0.48% (95% CI 0.36-0.63) and 2.16% (95% CI 1.85-2.51), respectively. HIV-related factors associated with incident NVAF included baseline CD4 count <200 (HR 1.84, 95% CI 1.20-2.80) and initial ART including protease inhibitors (HR 1.56, 95% CI 1.14-2.13) and/or integrase strand transfer inhibitors (HR 1.47, 95% CI 1.08-1.99). Additional associated factors included older age, Medicare, cardiology visit(s) in prior year, and co-morbid diseases including hypertension, hyperlipidemia, coronary and peripheral artery disease, prior stroke/transient ischemic attack, heart failure, and chronic kidney disease. Conclusions: In a large cohort of UREG living with HIV, both traditional and HIV-specific risk factors are associated with increased risk of incident NVAF. Interventions to mitigate NVAF risk in this population will require interdisciplinary, team-based approaches.

Investigation on improving immunologic reconstitution insufficiency using DiwuYanggan capsules in AIDS patients.

This study aimed to explore the mechanism of action of DiWuYangGan (DWYG) capsule in improving Immunological non-responder (INR) by analyzing the active ingredients of DWYG. The study employed a randomized, controlled, double-blind, single-simulation method. Patients were randomly divided into control and trial groups and treated with the primal highly effective antiretroviral therapy. To demonstrate the effect of DWYG on INR, patients in the control group were administered simulated DWYG, whereas patients in the trial group were administered DWYG capsules (ChiCTR1900024673). The chemical composition of DWYG was analyzed using ultra-performance liquid chromatography-high-resolution mass spectrometry. Potential targets of DWYG in the treatment of INR were identified and predicted using network pharmacology and molecular docking. The molecular mechanisms underlying the effects of DWYG were validated using a peripheral blood monocyte model. The CD4:CD8 ratio in the trial group was significantly higher than that in the control group (p < 0.01). A total of 210 DWYG compounds were identified and network pharmacology revealed 182 potential therapeutic targets for DWYG and INR. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the toll-like receptor signaling pathway is one of the key pathways. This study demonstrated that DWYG reduced the expression level of TLR4 and the levels of IL-2, IL-10, and TNF-α, which are important cytokines involved in the immune response. The efficacy of DWYG in the treatment of INR confirmed the potential practical components of DWYG. Moreover, the results of network pharmacology and experimental validation showed that DWYG could restore the immune function of acquired immune deficiency syndrome patients by inhibiting the expression of TLR4 and related signaling pathways and the overactivation of immune function. https://www.chictr.org.cn/index.html, identifier ChiCTR1900024673.

Non-AIDS defining cancers in HIV-infected individuals: a concise review

Non-acquired immunodeficiency syndrome (AIDS)-defining cancers (NADCs) present a growing concern in human immunodeficiency virus (HIV)-infected individuals, impacting morbidity and mortality rates. This paper synthesizes current epidemiological data and explores the multifaceted relationship between HIV infection and NADC risk. Epidemiological studies indicate a shifting landscape of cancer incidence among HIV-infected populations, with a notable rise in NADCs over recent decades. Factors such as prolonged life expectancy due to effective antiretroviral therapy (ART) and aging of the HIV-infected population contribute to this trend. Despite the overall decline in AIDS-defining cancers, NADCs have emerged as a significant cause of morbidity and mortality in HIV-infected individuals. Immunodeficiency, chronic inflammation, and oncogenic viral co-infections, such as human papillomavirus and hepatitis C virus, compound the risk of developing NADCs. Diagnostic challenges persist, with delayed detection and suboptimal management contributing to poor outcomes. Treatment modalities for NADCs in HIV-infected individuals require careful consideration, balancing cancer-directed therapy with potential interactions with ART and immune reconstitution. Prevention strategies, including cancer screening and lifestyle modifications, are crucial in mitigating the burden of NADCs in this population. As the landscape of HIV care continues to evolve, understanding the epidemiology and clinical characteristics of NADCs is imperative for optimizing clinical management and improving outcomes in HIV-infected individuals.

The impact of HIV antiretroviral therapy on gut microbiota: the need for well-designed longitudinal studies.

Human immunodeficiency virus (HIV) infection remains a major public health concern despite a significant decline in HIV-related mortality and morbidity. These significant advances are linked mostly to effective antiretroviral therapy (ART). However, these treatments are not without consequences on other microorganisms in our body, especially when they must be used for life. Balanced gut microbiota is essential for maintaining human health through symbiotic relationship with the host cells. This review focuses on ART and its potential impact on the intestinal microbial population of HIV-infected individuals. Therefore, we retrieved studies focusing on the impact of HIV ART on the gut microbiota, that were published from 2010 to 2021. It was observed that most studies on HIV ART and associated gut microbiota have been cross-sectional, and the findings, in general, showed significant damages caused by the ART to the gut microbial community (dysbiosis), with the impact varying in different studies. These changes also revealed dysfunction in microbial translocation and some immune markers, including T lymphocyte rates and the overall inflammation balance. There are significant gaps in our understanding of the impact of HIV ART on gut microbiota. Thus, a longitudinal study is likely needed with a considerable sample size from different settings and classes of ART to better understand the impact of HIV ART on the gut microbiota, and develop remedial (restorative) and adjunctive host-directed strategies during HIV ART.

Large-scale proteomic profiling reveals characteristic HIV-specific druggable protein signatures associated with incident heart failure

Abstract Background Compared with the general population, persons with HIV suffer from an augmented risk of both systolic and diastolic heart failure despite effective antiretroviral therapy [1]. While inflammatory and coagulation markers are thought to be involved in this increased risk, other contributing mechanisms, such as pro-inflammatory protein networks, remain to be elucidated. Purpose To identify novel protein predictors of incident heart failure events in the longitudinal Veterans Aging Cohort Study Biomarker Cohort of United States Veterans with HIV (PLWH; n = 1525) and without HIV (PWoH; n = 853) and to assess the functional relatedness of these proteins in PLWH. Methods We characterized the plasma proteome of PLWH and PWoH using an aptamer-based platform and assessed univariable associations with incident heart failure. Druggable proteins were identified using the Therapeutic Target Database [2]. We built a protein interaction network querying significant proteins (q-value &amp;lt;0.05) using Cytoscape for the Retrieval of Interacting Genes/Proteins (STRING) database [3]. To focus on densely connected core proteins, we used the mcl clustering method and identified a subnetwork of approximately 77 proteins. Over-representation analysis was performed for the core network by identifying enriched gene sets using Gene Ontology biological processes and WikiPathways. Final results are filtered based on a false discovery rate (FDR) threshold of 0.05. Results Of 4926 plasma proteins, 441 proteins in all PLWH and 706 in those with well-controlled HIV (viral load &amp;lt;200 copies/mL) were significantly associated with incident heart failure, compared with only 142 among PWoH (Figure 1A). Of the top 50 proteins most significantly associated with heart failure, 21 were druggable in PLWH and 14 in PWoH; only 5 druggable markers were shared, while 16 were unique to HIV (Table 1). Pleiotrophin, a pro-angiogenic, pro-inflammatory cytokine that induces tumor necrosis factor- (TNF) α, interleukin- (IL) 1β, and IL-6 expression and has been implicated in cardiomyocyte apoptosis [4,5], had the highest hazard ratio (HR) for incident heart failure (HR = 4.7; p = 1.6E-20; q = 1.7E-18) in PLWH. The most significant enriched protein pathway included 36 genes involved in chemotaxis (FDR = 1.3E-30); 3 of the 21 druggable targets (pleiotrophin, ephrin-A5, and ephrin type-A receptor 2) were represented in this pathway (Figure 1B). Ephrin signaling pathways, which are involved in cell adhesion, differentiation, and proliferation [6], have not previously been implicated in heart failure, nor in HIV. Subnetwork analysis of druggable proteins demonstrated that ephrin-signaling, IL-15, and TNF pathways were functionally interconnected (Figure 1C). Conclusions Our findings indicate that there may be unique pro-inflammatory pathways characteristic of HIV-associated cardiomyopathy that merit further study as dedicated pharmacologic targets and/or risk markers in this population.

Prevalence of metabolic dysfunction-associated steatotic liver disease in people living with HIV and on antiretroviral treatment: A systematic review and meta-analysis protocol.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common hepatic condition globally. The prevalence of MASLD continues to increase, paralleling the consistent rising rates of risk factors such as obesity and type 2 diabetes. Literature suggests that human immunodeficiency virus-infected (HIV-infected) individuals may have an increased risk of developing MASLD due to a complex interplay of factors including antiretroviral therapy. Since the development and widespread use of effective antiretroviral therapy (ART), HIV-induced liver disease has continued to be the predominant cause of liver-related morbidity and mortality. This protocol serves to narrate the methods that will be employed in conducting the published literature search for the systematic review and meta-analysis which will report on the global prevalence of MASLD on people living with HIV and on ARV treatment. The search of literature will be done using search engines or electronic databases including PubMed, Google Scholar, African Journal Online, and ResearchGate. Specific keywords will be used to search literature that has reported on the prevalence of MASLD among HIV patients receiving antiretroviral treatment, this will ensure the reproducibility of the study. Cross-sectional and longitudinal observational studies, retrospective cohort studies, clinical trial studies, meta-analyses, and systematic reviews that were published in the English language from 1990 to 2024 will be included. Animal studies will be excluded. Three independent reviewers will conduct the selection process and select studies that meet the eligibility criteria. A quality assessment tool, Downs and Blacks will be used to assess the risk of bias of the selected studies. A review manager will be used for meta-analysis of collected data and the Grading of Recommendations Assessment, Development, and Evaluation tool will assess the strength of evidence. The review will not require ethical clearance as it will only include data that is publicly available in published reports. The results of this review will be disseminated through publications. This study is registered with PROSPERO (CRD42024516814).

Fecal microbiota transplantation alters the proteomic landscape of inflammation in HIV: identifying bacterial drivers

BackgroundDespite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation and increased morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplantation (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo.MethodsThis double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo treatment over 8 weeks on systemic inflammation in 29 PWH receiving stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected, and their individual stools were used for FMT capsule preparation. Proteomic changes in 345 inflammatory proteins in plasma were quantified using the proximity extension assay, with samples collected at baseline and at weeks 1, 8, and 24. Concurrently, we characterized shifts in the gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with microbiome composition and functionality over time using linear mixed models.ResultsFMT significantly reduced the plasma levels of 45 inflammatory proteins, including established mortality predictors such as IL6 and TNF-α. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including in the expression of proteins such as CCL20 and CD22. We identified changes in 46 proteins, including decreases in FT3LG, IL6, IL10RB, IL12B, and IL17A, which correlated with multiple bacterial species. We found that specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae families, and the Clostridium genus, in addition to their associated genes and functions, were significantly correlated with changes in inflammatory markers.ConclusionsTargeting the gut microbiome through FMT effectively decreased inflammatory proteins in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions.3bGeWVUV_8zBqrmtjgQWmWVideo

People with HIV exhibit spectrally distinct patterns of rhythmic cortical activity serving cognitive flexibility

Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29–76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4–8 Hz), alpha (10–16 Hz), and gamma (74–98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.

Mechanisms underlying the development of type 1 diabetes in ART-treated people living with HIV: an enigmatic puzzle.

The immunopathogenesis of HIV infection remains poorly understood. Despite the widespread use of effective modern antiretroviral therapy (ART), people living with HIV (PLWH) are known to develop several comorbidities, including type 1 diabetes (T1DM). However, the etiology and critical mechanisms accounting for the onset of T1DM in the preceding context remain unknown. This article proposes to address this topic in order to provide further understanding and future research directions.

SARS-CoV-2 Modulation of HIV Latency Reversal in a Myeloid Cell Line: Direct and Bystander Effects.

Coronavirus disease 2019 (COVID-19) might impact disease progression in people living with HIV (PLWH), including those on effective combination antiretroviral therapy (cART). These individuals often experience chronic conditions characterized by proviral latency or low-level viral replication in CD4+ memory T cells and tissue macrophages. Pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, can reactivate provirus expression in both primary cells and cell lines. These cytokines are often elevated in individuals infected with SARS-CoV-2, the virus causing COVID-19. However, it is still unknown whether SARS-CoV-2 can modulate HIV reactivation in infected cells. Here, we report that exposure of the chronically HIV-1-infected myeloid cell line U1 to two different SARS-CoV-2 viral isolates (ancestral and BA.5) reversed its latent state after 24 h. We also observed that SARS-CoV-2 exposure of human primary monocyte-derived macrophages (MDM) initially drove their polarization towards an M1 phenotype, which shifted towards M2 over time. This effect was associated with soluble factors released during the initial M1 polarization phase that reactivated HIV production in U1 cells, like MDM stimulated with the TLR agonist resiquimod. Our study suggests that SARS-CoV-2-induced systemic inflammation and interaction with macrophages could influence proviral HIV-1 latency in myeloid cells in PLWH.

Advancing research and development of anti-infectives for children: A clinical development perspective

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programmes, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged <4 wk). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarise challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.

Photogallery. Human papillomavirus infection of the skin and mucous membranes in people living with HIV

The human papillomavirus is ubiquitous. It is estimated that over a third of people with apparently healthy skin are carriers of human papillomavirus. HIV-associated immunodeficiency contributes to the manifestation of clinical symptoms of human papillomavirus infection. Against the background of severe (the number of CD4+ T-lymphocytes below 200 cells/μl) and pronounced (CD4+ T-lymphocytes from 200 to 349 cells/μl) immunodeficiency caused by HIV infection (human immunodeficiency virus), the period of persistence of human papillomavirus is longer, and the clinical picture and course of human papillomavirus infection can significantly differ compared to HIV-positive individuals with intact immunity and people without HIV. At the same time, formations on the skin and mucous membranes are often multiple and can be characterized by rapid growth, large size, location outside the typical localization, resistance to treatment, recurrent course, and lack of tendency to spontaneous regression. Taking antiretroviral drugs for the treatment of HIV infection has a generally beneficial effect on the clinical course and prognosis of viral warts; With regard to anogenital warts, the researchers’ conclusions are not so clear. A number of experts believe that viral-immunological control of HIV infection may not be sufficient to successfully combat venereal warts. The photogallery presents various clinical types of viral and anogenital (venereal) warts in people living with HIV. Each of them is assigned one of the variants of the stage of secondary diseases of HIV infection (4A, 4B or 4V according to its Russian clinical classification) depending on the severity of concomitant opportunistic diseases. In all clinical cases, with the exception of the last one, patients experienced severe or pronounced immunodeficiency and progression of HIV infection in the absence of antiretroviral therapy. In the last observation, giant Buschke–Levenstein condyloma developed with a slight immunodeficiency against the background of effective antiretroviral therapy.

Evaluating the modulation of peripheral immune profile in people living with HIV and (Neuro)cysticercosis.

The parasitic infection caused by Taenia solium represents a significant public health concern in developing countries. Larval invasion of body tissues leads to cysticercosis (CC), while central nervous system (CNS) involvement results in neurocysticercosis (NCC). Both conditions exhibit diverse clinical manifestations, and the potential impact of concomitant HIV infection especially prevalent in sub-Saharan Africa on peripheral and CNS immune responses remains poorly understood. This study aimed to identify the potential impact of HIV coinfection in CC and NCC patients. A nested study within a cross-sectional analysis in two Tanzanian regions was performed and 234 participants (110 HIV+ and 124 HIV-) were tested for cysticercosis antibodies, antigens, CD4 counts and serum Th1 and Th2 cytokines via multiplex bead-based immunoassay. 127 cysticercosis seropositive individuals underwent cranial computed tomography (CCT) and clinical symptoms were assessed. Multiple regression analyses were performed to identify factors associated with cytokine modulation due to HIV in CC and NCC patients. Serologically, 18.8% tested positive for cysticercosis antibodies, with no significant difference HIV+ and HIV+. A significantly higher rate of cysticercosis antigen positivity was found in HIV+ individuals (43.6%) compared to HIV- (28.2%) (p = 0.016). CCT scans revealed that overall 10.3% had active brain cysts (NCC+). Our study found no significant changes in the overall cytokine profiles between HIV+ and HIV- participants coinfected CC and NCC, except for IL-5 which was elevated in HIV+ individuals with cysticercosis. Furthermore, HIV infection in general was associated with increased levels of pro-and some anti-inflammatory cytokines e.g. TNF-α, IL-8, and IFN-γ. However, based on the interaction analyses, no cytokine changes were observed due to HIV in CC or NCC patients. In conclusion, while HIV infection itself significantly modulates levels of key cytokines such as TNF-α, IL-8, and IFN-γ, it does not modulate any cytokine changes due to CC or NCC. This underscores the dominant influence of HIV on the immune system and highlights the importance of effective antiretroviral therapy in managing immune responses in individuals coinfected with HIV and CC/NCC.