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The intestinal mucosa in individuals with chronic human immunodeficiency virus (HIV) infection remains a site of viral persistence and immune dysregulation, even with prolonged suppressive antiretroviral therapy (ART). While biomarkers of mucosal damage and microbial translocation offer valuable correlative insights, the underlying mechanisms remain incompletely understood. Immunoregulatory galectins are implicated in HIV persistence and pathogenesis and play critical roles in intestinal inflammation and host-microbiome homeostasis. Here, we leveraged archival samples and data from an anti-alpha 4 beta 7 immunotherapy study of simian immunodeficiency virus (SIV)-infected rhesus macaques to investigate the relationships between circulating and gut mucosal galectins 1, 3, and 9, and barrier integrity, by tracking levels of tight junction proteins, and SIV viral load assessment of RNA and DNA levels in tissues. Elevated plasma levels of galectin-9 during peak viremia, ART suppression, ART interruption, and at necropsy were significantly correlated with SIVgag DNA levels in the ascending colon during necropsy. Several galectins were significantly reduced in the ascending colon and duodenum in ART-treated SIV-infected macaques compared to viremic animals and were related to tight junction disruptions. These findings suggest mucosal SIV burden and impaired gut integrity may be influenced by changes due to circulating and tissue galectins, making them potential therapeutic targets to restore gut homeostasis.

We evaluated the magnitude and function of antibody responses to seasonal influenza vaccination in individuals with HIV receiving ART compared with individuals without HIV. In a prospective cohort of 78 adults, influenza strain-specific IgG levels were measured up to one-year post-vaccination. Linear mixed-effects models assessed longitudinal trends. IgG levels peaked at two weeks and declined gradually in both groups. HIV status did not significantly influence antibody magnitude or neutralizing activity, and H1N1 antibody levels correlated with neutralization titers. These findings demonstrate robust, durable, and functional humoral response in well-controlled HIV, supporting the effectiveness of annual influenza vaccination in this population.

Background: Older adults (> 65 years) residing in long-term care facilities (LTCFs) are at elevated risk of severe outcomes from respiratory infections. Infections often remain undetected or present atypically in this population, leading to underdiagnosis. Our study aimed to estimate the respiratory virus infection burden, independent of symptom presentation, among older adults in Swedish LTCFs in the post-pandemic period (2021–2024).

Methods: We leveraged capillary blood samples and coupled national registry data from 1622 LTCF residents (median age = 87). A multiplex platform was used to quantify antigen-specific IgG and IgM responses to RSV (pre-/post-F, strain A-specific G-protein), influenza-A (H1N1 and H3N2 HA), influenza-B (HA) and SARS-CoV-2 (spike). Linear mixed-effects models were used to demonstrate the dynamics of antibody levels over time, adjusted for age, sex and comorbidities.

Results: RSV-specific antibody responses peaked in spring 2022 (p < 0.001), suggesting an impact of relaxed COVID-19-related restrictions on RSV exposure at LTCFs. RSV-specific antibodies subsequently declined over time until an increase during autumn 2023 (p < 0.001). Geographic variation in pre-F antibody levels suggested localised RSV outbreaks. The total estimated RSV burden at LTCFs was markedly higher than official reports of the Swedish Public Health Agency. Influenza antibody dynamics reflected seasonal trends and were strongly influenced by annual vaccination. A random forest classifier incorporating serological profiles with demographics, location and comorbidities significantly outperformed a model without serological data (AUC-ROC = 0.67 vs. 0.58), although discriminatory performance remained modest. Higher levels of RSV pre-F antibodies in autumn 2021 were associated with increased one-year mortality in logistic regression (OR = 1.43, p = 0.024). Exploratory survival analysis indicated a trend that elevated levels of RSV pre-F antibodies during low population immunity may confer a transiently elevated early hazard of death, although this did not reach statistical significance (HR = 4.50, p = 0.087).

Conclusions: We observed substantial respiratory virus circulation among older adults in Swedish LTCFs and show that RSV burden is under-reported. The results highlight a need for further research into the role of RSV pre-F antibody levels in preventing severe outcomes, potentially via vaccination of LTCF residents. Our scalable serological surveillance system is a valuable approach to detect respiratory infections in LTCFs, independent of symptom presentation or healthcare-seeking behaviour.

Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation, and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/μl, n = 34 or immune competent: CD4 >500 cells/μl, n = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantly higher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significant after adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classification of individuals with poor CD4 trajectories. In summary, we identified a novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART.

Importance: It is essential to track immune perturbations related to insufficient CD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatory soluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.

Objective: Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored.

Design: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naive (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests.

Methods: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann – Whitney U tests to determine group-wise differences, Spearman’s correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers.

Results: Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFa, MCP-1, IP-10, IL-10) and activated CD8+ T cells (all P < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837].

Conclusion: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV. 

Multiple cellular HIV reservoirs in diverse anatomical sites can undergo clonal expansion and persist for years despite suppressive antiretroviral therapy, posing a major barrier toward an HIV cure. Commonly adopted assays to assess HIV reservoir size mainly consist of PCR-based measures of cell-associated total proviral DNA, intact proviruses and transcriptionally competent provirus (viral RNA), flow cytometry and microscopy-based methods to measure translationally competent provirus (viral protein), and quantitative viral outgrowth assay, the gold standard to measure replication-competent provirus; yet no assay alone can provide a comprehensive view of the total HIV reservoir or its dynamics. Furthermore, the detection of extant provirus by these measures does not preclude defects affecting replication competence. An accurate measure of the latent reservoir is essential for evaluating the efficacy of HIV cure strategies. Recent approaches have been developed, which generate proviral sequence data to create a more detailed profile of the latent reservoir. These sequencing approaches are valuable tools to understand the complex multicellular processes in a diverse range of tissues and cell types and have provided insights into the mechanisms of HIV establishment and persistence. These advancements over previous sequencing methods have allowed multiplexing and new assays have emerged, which can document transcriptional activity, chromosome accessibility, and in-depth cellular phenotypes harboring latent HIV, enabling the characterization of rare infected cells across restrictive sites such as the brain. In this manuscript, we provide a review of HIV sequencing-based assays adopted to address challenges in quantifying and characterizing the latent HIV reservoir. 

Galectin-9 (Gal-9) is a β-galactoside binding lectin known for its immunomodulatory role in various microbial infections. Gal-9 is expressed in all organ systems and localized in the nucleus, cell surface, cytoplasm and the extracellular matrix. It mediates host-pathogen interactions and regulates cell signalling via binding to its receptors. Gal-9 is involved in many physiological functions such as cell growth, differentiation, adhesion, communication and death. However, recent studies have emphasized on the elevated levels of Gal-9 in autoimmune disorders, viral infections, parasitic invasion, cancer, acute liver failure, atopic dermatitis, chronic kidney disease, type-2 diabetes, coronary artery disease, atherosclerosis and benign infertility-related gynecological disorders. In this paper we have reviewed the potential of Gal-9 as a reliable, sensitive and non-invasive biomarker of disease severity. Tracking changes in Gal-9 levels and its implementation as a biomarker in clinical practice will be an important tool to monitor disease activity and facilitate personalized treatment decisions.