The primary route of HIV transmission is across mucosal tissues; therefore, developing a protective mucosal vaccine is a top priority. In a pilot study, using a macaque model, we delivered HIV gp140 envelope glycoprotein and SIVmac239 P55 Gag and Nef antigens using heterologous prime/boost via the intranasal route with a soybean oil-based nanoemulsion (NE) adjuvant and through the intramuscular route with the AS01B adjuvant system to generate enhanced cell-mediated immunity. We used a NE adjuvant to promote gut-homing cell-mediated immunity and the AS01B system to enhance humoral immune responses. Following intrarectal challenge with SHIV 4MTF.tHy, vaccinated macaques acquired the virus but experienced lower viral loads in plasma (P=0.003) and CSF (P=0.001), and potent polyfunctional gag-specific (CD107a+, IFNγ, TNFα+) responses across diverse lymph nodes. Significant antibody-dependent complement deposition (ADCD) and antibody-dependent cellular phagocytosis (ADCP) responses were induced, and gut-microbiome crosstalk could be modulated and showing reduced SHIV-dysbiosis. Notably, vaccination preserved mucosal all-trans retinoic acid levels (atRA) (p<0.05). However, no significant differences were observed for antibody responses between vaccinated and unvaccinated macaques. In summary, the induced gut-homing properties by the NE adjuvant are effective at generating cell-mediated immunity and reducing viral set points and warrant further investigations as a mucosal adjuvant in HIV vaccine design.

Post-acute sequelae of SARS-CoV-2 infection, or Long-COVID, affects millions globally and is characterized by persistent symptoms affecting multiple organs, yet the underlying mechanisms remain poorly defined. Here, we used Golden Syrian Hamsters (GSH) infected with the SARS-CoV-2 to investigate how sex and age shape viral persistence, organ-specific pathology, immune responses, and neurological outcomes during acute infection and Long-COVID. We show that during Long-COVID, viral RNA persists only in the lungs of male hamsters. Lung pathology revealed sustained inflammation and tissue remodeling, with young females exhibiting greater fibrosis. Transcriptomic profiling across brain, lung, and heart identified pronounced sex- and age-dependent regulation of gene expression spanning immune, neuroinflammatory, and neurotransmitter signaling pathways. These transcriptomic alterations were accompanied by sex-specific behavioral changes and persistent microstructural remodeling in cognition-associated brain regions. Additionally, SARS-CoV-2 altered α-synuclein homeostasis and microglial activation alongside gut microbiome composition in a sex- and age-dependent manner. Together, our findings demonstrate that, in GSH Long-COVID is strongly modulated by sex and age, influencing viral RNA persistence, immune and neurobiological responses, and gut microbiota composition mirroring clinical outcomes reported in human cohorts. This study establishes SARS-CoV-2-infected GSH as a model for dissecting the mechanisms of Long-COVID and informing targeted prevention strategies.

Opioid use is disproportionately high among People with HIV (PWH). Although combined antiretroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell RNA sequencing (scRNA-seq) of cerebrospinal fluid (CSF) immune cells to explore how opioid mediated transcriptomic alterations impact neuroinflammatory signaling among PWH using the SIV/rhesus macaque model. Herein, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. We observed all major immune cells in CSF, including CD4 + TCM cells, CD4 + TEM cells, CD8+ naïve T cells, CD8 + TCM cells, CD8 + TEM cells, CD14 + Monocytes, CD16 + Monocytes, NK cells, and B cells. Additionally, we found that morphine-mediated relative increase in CD4 + TCM, Treg, and a reduction in CD8 + TEM cell population prior to SIV infection. Chronic use of morphine was associated with a Th1/Th2 T-cell imbalance with a dominance of the Th2 population. In CSF cells from morphine-dependent RMs, there was dysregulation of genes involved in T-cell receptor signaling pathways, apoptosis, PI3K-Akt signaling pathway, cellular senescence, oxidative phosphorylation, and multiple neurodegenerative disorders. The contribution of different cell populations in these processes evolved across disease stages. During the chronic stage of the disease, the expression of disease-associated microglia (DAM) signature genes were significantly up or down regulated in monocytes. Further, cell-cell receptor-ligand interaction analysis revealed altered number of intercellular interactions and signaling strength in morphine vs. saline-administered animals. Specifically, for the CD14 + monocyte populations, the intra/inter-cell communication involving ligand-receptor pairs, including APOE-TREM2, APP (TREM2 + TYROBP), APP-CD74, SPP1−(ITGA4 + ITGB1), and CCL signaling pathways, remains significantly altered in the morphine-dependent macaques. Chronic opioid exposure reprograms CSF immune cells, creating a Th1/Th2 T-cell imbalance and polarizing monocytes toward a DAM-like state. This cell type specific transcriptomic signature is associated with progressive neuroinflammatory signaling in morphine-dependent macaques, and may have implications for neuroinflammatory and neurodegenerative phenotypes observed in PWH.

Post-Acute Sequelae of COVID-19 (PASC) is increasingly associated with long-term cardiovascular complications, yet the underlying molecular mechanisms, remain poorly understood. Host genetic susceptibility is likely to modulate post-viral cardiac vulnerability, but its interaction with persistent molecular remodelling after SARS-CoV-2 infection has not been systematically investigated. We employed an integrative multi-omics framework combining a pilot genome-wide association study (GWAS) of Indian PASC patients with post-acute cardiac transcriptomic profiling from a SARS-CoV-2-infected Golden Syrian hamster (GSH) model. GWAS signals were mapped to differentially expressed genes, followed by integrative stratification based on genetic risk and transcriptional perturbation. Consequences of genetic variations were quantified using structural bioinformatics approaches involving Molecular Dynamics. GWAS identified multiple loci associated with PASC, including genes implicated in arrhythmia, myocardial remodelling, vascular signaling, and cardiometabolic regulation. Integration with post-acute cardiac transcriptomics of GSH revealed 15 genes with convergent genetic and transcriptional evidence. Although no global monotonic correlation was observed between genetic risk and expression magnitude, genes segregated into distinct mechanistic classes, including genetically primed and virally activated drivers, inherited susceptibility genes with minimal post-viral expression change, and virus-driven transcriptional responses. Structural and molecular dynamics analyses of EYA2, TTN, VAV2, and KCNQ1 demonstrated variant-specific destabilization affecting myocardial stress adaptation, sarcomeric mechanics, vascular signalling, and cardiac electrical stability. These findings support a model where inherited genetic susceptibility interacts with persistent post-infectious cardiac remodelling to drive chronic cardiovascular dysfunction observed in PASC patients. Integrative host genomics provides a mechanistic framework for risk stratification and precision surveillance of post-COVID cardiovascular disease (CVD).

Long-COVID, also referred to as post-acute sequelae of COVID-19 (PASC), is a heterogeneous disorder encompassing more than 200 reported symptoms that commonly affect the respiratory and nervous systems. Emerging clinical evidence indicates that unresolved lung inflammation, vascular injury, and immune dysregulation drive sustained neuroinflammation and impaired neurocognitive function in Long-COVID patients. Given the ethical and logistical constraints of human studies, biologically relevant animal models are essential for understanding the mechanisms and for evaluating therapeutic strategies against Long-COVID. In this review, we synthesize current evidence from preclinical animal models of Long-COVID, with a particular emphasis on the Golden Syrian Hamsters. Golden Syrian Hamsters are naturally susceptible to SARS-CoV-2 infection without the need for genetic modification and recapitulate key features of human disease, including robust viral replication, pulmonary pathology, and inflammatory response during acute infection. Importantly, accumulating evidence demonstrates that Golden Syrian Hamsters develop persistent post-acute abnormalities along the lung–brain-immune axis, including impaired alveolar repair, fibrotic lung remodeling, neuroinflammation, viral or antigen persistence, and behavioral alterations that parallel core features of Long-COVID. We compare the strengths and limitations of Golden Syrian Hamsters with other commonly used pre-clinical animal models including mice, and non-human primates, highlighting differences in translational relevance, feasibility, and ability to model chronic lung-brain-immune axis dysfunction. While there are limitations, particularly regarding limited availability of immunological reagents and validated cognitive and behavioral assays, the Golden Syrian Hamsters offers a balanced and accessible platform for mechanistic studies of PASC. Overall, this review positions Golden Syrian Hamster as a robust translational model for investigating lung–brain–immune axis pathology in Long-COVID and for advancing the development of targeted therapeutic interventions.

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-α4β7 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.

Background:Opioid use is disproportionately high among People with HIV (PWH). Although combined anti-retroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell transcriptomic profiling of cerebrospinal fluid (CSF) immune cells to explore their functional characteristics in opioid mediated neurological disorders among PWH using the SIV/rhesus macque model. Methods:In this study, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-Seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. Results:We observed the presence of all major immune cells in CSF, including CD4 + TCM cells, CD4 + TEM cells, CD8+ naïve T cells, CD8 + TCM cells, CD8 + TEM cells, CD14 + Monocytes, CD16 + Monocytes, NK cells, and B cells. Additionally, we also demonstrated morphine-mediated relative increase in CD4 + TCM, Treg, and a reduction in CD8 + TEM cell population prior to SIV infection. Chronic use of morphine was associated with a Th1/Th2 T-cell imbalance with a dominance of the Th2 population. In CSF cells from morphine-dependent RMs, there was dysregulation of genes involved in T-cell receptor signaling pathways, apoptosis, PI3K-Akt signaling pathway, cellular senescence, oxidative phosphorylation, and multiple neurodegenerative disorders. The contribution of different cell populations in these processes evolved along with different stages of disease pathogenesis. In the chronic stage of the disease, the expression of disease-associated microglia (DAM) signature genes were significantly upregulated in monocytes. Further, cell-cell receptor-ligand interaction analysis revealed an altered number of intercellular interactions and signaling strength in morphine vs. saline-administered animals. Specifically, for the CD14 + monocyte populations, the intra/inter-cell communication involving ligand-receptor pairs, including APOE-TREM2, APP(TREM2 + TYROBP), APP-CD74, SPP1-(ITGA4 + ITGB1), and CCL signaling pathways, remains significantly altered in the morphine-dependent macaques. Conclusion:Chronic opioid exposure reprograms CSF monocytes toward a DAM state that persists despite ART-mediated viral suppression, driving maladaptive immune-glial crosstalk and progressive neurocognitive dysfunction in morphine-dependent macaques with possible implications for neuroinflammation and neurodegenerative disorders that are observed in PWH.

Hantaviruses are enveloped, negative-sense RNA viruses. Rodents serve as natural reservoirs, and spillover into humans causes hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. While transmission typically occurs by inhaling aerosolized rodent excreta, the Andes virus variant is capable of human-to-human transmission. A recent outbreak involving a person-to-person transmission cluster aboard the cruise ship MV Hondius has underscored the urgency of hantavirus preparedness. Immediate global pandemic risk remains low because sustained transmission requires prolonged close contact, and hantavirus has low environmental stability compared to other RNA viruses with pandemic potential. However, climate change, deforestation, and urbanization increase human-rodent interactions and spillover risks. Additionally, prolonged incubation in immunocompromised individuals, including people with Human Immunodeficiency Virus (PWH) and other chronic conditions, may facilitate viral adaptation, potentially leading to strains with enhanced transmissibility. We review hantavirus classification, epidemiology, transmission dynamics, immunopathology, treatment strategies, the urgent need for global surveillance, and accelerated vaccines and prophylactic development.

Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.

Background:Susceptibility to infectious diseases is a result of complex interactions between genomic, environmental, and clinical factors. COVID-19 severity and post-acute sequelae of COVID-19 (PASC) vary widely among individuals, yet its genetic determinants remain underexplored in Indian populations. In this article, we undertake an exploratory analysis to investigate candidate genetic variants and biological pathways underlying the clinical outcomes in COVID-19 severity and PASC. Methods:Sixty individuals with a history of COVID-19 were genotyped, and their data were supplemented with publicly available datasets from the Genome Asia 100K and Gujarat Biotechnology Research Centre. Two case-control genome-wide association study (GWAS) models were analyzed: (i) COVID-19 severity (mild/asymptomatic vs. severe) and (ii) an exploratory, hypothesis-generating GWAS for PASC (presence vs. absence of post-COVID-19 complications). Candidate genes identified here were further compared with RNA-sequencing datasets derived from brain and lung tissues of SARS-CoV-2-infected hamsters. The population-specific genetic risk for PASC was estimated using the polygenic risk score algorithm PRSice-2. Results:GWAS identified candidate genes common to both COVID-19 severity and PASC, including CNTNAP2, WWOX, and ADAMTS17, which are implicated in extracellular matrix remodeling and neurological and cognitive development. We identified 806 candidate genes shared between the severity and PASC cohorts. Of these, 30 protein-coding genes were associated with neuropsychiatric disorders, and 23 were linked to cardiovascular conditions. Notably, CACNA1C, SLC8A1, GRK5, PDE4B, and LRRK2 were identified in both categories, suggesting potential convergence of molecular pathways underlying neurological and cardiovascular dysfunction. Integration with transcriptomic data reinforced the involvement of shared molecular pathways disrupted by SARS-CoV-2 infection. Polygenic risk analysis revealed significant population-specific variation in genetic predisposition to PASC. Conclusion:Genetic susceptibility to severe COVID-19 and PASC in Indian populations appears to be linked to dysregulation of pathways central to cardiac and neurological function. These findings, derived from an exploratory PASC GWAS, provide preliminary insights into the molecular mechanisms that may underlie the post-viral sequelae. These emphasize the need for population-wide genomic studies to validate the candidate associations, better understand PASC risk, and facilitate the development of precision diagnostics and therapeutics.

Comprehensive estimation of COVID-19, including infection, death, excess mortality, case fatality rate (CFR), and infection fatality rate (IFR), is essential for understanding the pandemic's pattern. The location-specific estimates of infection, death, and excess mortality of COVID-19 from January 1, 2020, to February 11, 2024, and we have cumulative infections and cumulative deaths worldwide. Using the WHO dataset and Our World in Data, we estimated infection, mortality, excess mortality, CFR, and IFR in 234 countries and territories during COVID-19. We found a cumulative 0.774631 billion infections and 7.031 million deaths worldwide. The global highest infection peak was noted on December 25, 2022, with 42.5 million infection cases. Similarly, considering region-wise infection, cumulative infection was highest in Europe (428.4 M) and lowest in Africa (9.6 M). The global highest death peak was noted on January 24, 2021, with 103.7 K million deaths; this might be due to the spread of the Delta variant in some regions of Asia. Similarly, region-wise mortality was calculated. The considerable excess mortality pattern was noted in Europe, South America, and North America. Decreasing trends in excess mortality were noted in Oceania, Asia, and Africa. Our studies could be beneficial in formulating public health strategies and implementing policies about those regions, which are crucial to global health and will help future pandemics.

Human metapneumovirus (hMPV) is a seasonal respiratory virus that typically causes mild, flu-like symptoms. In some cases, it can lead to severe respiratory complications, such as pneumonia, bronchitis, and bronchiolitis, often requiring hospitalization. Recently, a surge in hMPV cases has been reported in China and other countries, raising concerns about a potential pandemic scenario reminiscent of COVID-19. This review explores the genomic structure, replication cycle, genetic diversity, and evolutionary trajectory of hMPV. It also discusses host immune responses and the available animal models to study pathogenesis and to screen for potential vaccines and antivirals. Additionally, we examine the shifting seasonal trends in hMPV circulation, evaluate the low pandemic risk posed by existing hMPV clades, and underscore the need for continued vaccine and antiviral development. Finally, we advocate for strengthened global surveillance, especially in low- and middle-income countries, as a critical strategy to mitigate the risks posed by emerging hMPV clades.

The vaginal microbiome plays a crucial role in maintaining mucosal integrity and mitigating pathogen transmission, yet its comprehensive characterization remains challenging due to limited sampling and analysis methods. In this study, we aimed to characterize bacterial and fungal taxa diversities in the vaginal microbiomes of Simian Human Immunodeficiency (SHIV)-infected rhesus macaques, as well as their metabolic activities, using three sampling methods. The cervicovaginal lavage (CVL), vaginal swab, and vaginal mucosal tissue methods offer novel insights into microbial diversity and their potential impacts on HIV transmission. Using 16S rRNA and Internal Transcribed Spacer (ITS) sequencing, we assessed bacterial and fungal community composition and abundances, respectively, across all sampling methods. PICRUSt2 was used for functional predictions, and a modified glycosidase assay to further characterize glycan-degrading enzymatic activity in CVL samples. Our findings reveal that tissue samples were uniquely enriched for microbial taxa such as Prevotella spp. and Helicobacter spp., showing notable abundance differences compared to CVL and swab samples. Tissue samples exhibited higher alpha diversity and distinct metabolic prediction profiles, particularly elevated sialidase activity. While fewer differences were found in fungal microbiome composition and diversity, marked correlations were observed between bacterial and fungal taxa, emphasizing complex interkingdom interactions. These results highlight the significance of sampling methods in microbial ecology studies, which should be carefully considered due to their potential influence on pathogen transmission risk.

Latent viral reservoirs remain a major barrier to curing HIV-1, with the long-terminal repeat (LTR) and Tat playing crucial roles in regulating viral transcription. Subtype-specific transcription factor binding site (TFBS) variations within the LTR significantly influence latency and reservoir stability. In earlier work, we identified HIV-1C LTR variants with duplicated TFBS motifs, including NF-κB, AP1, RBEIII, and TCF-1α/LEF-1. Using five cell models, including Jurkat and primary CD4⁺ T cells, we compared canonical R-LTR and variant R2-LTR strains. Across sub-genomic reporters, single-round infections, and full-length viral vectors, we found that the balance between RBEIII and NF-κB motifs governs stability of latency. The ‘two-viruses-one-cell’ system that normalized confounding environmental factors further revealed that latency is primarily controlled by intrinsic transcriptional circuits rather than external stimuli. In longitudinal studies of HIV-1⁺ individuals from acute and chronic infection phases, we observed dominant R strains during early infection and the spontaneous emergence of R2 strains in nearly half of chronic-phase subjects, a process accelerated by ART. Upon CD4⁺ T cell activation, R strains preferentially rebounded, while R2 strains showed strong resistance to reversal, even in subjects harbouring a co-infection. Together, these findings establish the clinical significance of LTR variation in latency regulation and identify the R2 phenotype as a critical determinant of reservoir persistence. These results underscore the importance of addressing reservoir heterogeneity in cure strategies, particularly in HIV-1C-prevalent regions. ### Competing Interest Statement The authors have declared no competing interest. * TFBS : Transcription factor binding site HIV-1C : HIV-1 subtype C LTR : Long Terminal Repeats C-LTR : HIV-1C LTR NGS : Next-generation sequencing RT-PCR : Reverse transcription polymerase chain reaction MTRC : Master transcription regulatory circuit TFC : Transcription factor complex PBMC : Peripheral Blood Mononuclear Cell TILDA : Tat/Rev Induced Limiting Dilution Assay gDNA : genomic DNA cDNA : complementary DNA pRNA : Plasma RNA LFU : Lost-to-Follow-Up PTC : Post-Treatment Control ART : Anti- Retroviral Therapy Department of Biotechnology, https://ror.org/03tjsyq23, BT/PR7359/MED/29/651/2012, BT/NETHERLANDS/RG/40/2015 United States Agency for International Development, AID-OAA-A-16-00032 Science and Engineering Research Board, https://ror.org/03ffdsr55, SPR/2021/000338-G Gennova Biopharmaceuticals Ltd., Corporate Social Responsibility Funds

Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Furthermore, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized that combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points after ATI. Additionally, following ATI, dual-treated RMs showed immunological benefits, including T cell preservation and lower PD-1+ central memory T cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) after ATI. Finally, 16S rRNA-Seq revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.

BackgroundThe global burden of latent tuberculosis infection (LTBI), with one-third of the population, poses a significant challenge in the diagnosis and treatment of TB. Household contacts (HHCs) of active TB-infected individuals are one of the major high-risk groups for whom early screening and timely intervention are highly critical to interrupt TB transmission. The subclinical latent infection transitions into active TB disease due to multiple factors. Laboratory diagnostic markers inherent to interferon-gamma release assay (IGRA) positive and negative HHCs may help predict the risk of LTBI and subsequent reactivation. The study aims to identify biochemical and hematological diagnostic markers associated with HHCs and their IGRA status, and to explore the likelihood of clinical laboratory analytes and platelet-associated parameters for use as surrogate markers of subclinical inflammation in LTBI.MethodsA cross-sectional study was carried out on the HHCs of active TB-infected individuals and healthy controls to determine the association of biochemical and hematological markers with their IGRA status. Blood samples collected from the participants were tested for different laboratory parameters and analyzed by binary regression analysis to determine their efficacy in predicting the development of LTBI.ResultsErythrocyte sedimentation rate (ESR), mean platelet volume (MPV), D-dimer, platelet-large cell ratio (P-LCR), and platelet distribution width (PDW) were significantly high among LTBI-positive individuals. Among different markers, significant association with LTBI was observed with ESR, PDW, and P-LCR, with their AUC and p values reported as 0.6950 (p=0.0095**), 0.7333 (p=0.0469*), 0.7150 (p=0.0042**), respectively. Binary regression analysis revealed significantly higher odds of LTBI in individuals with elevated ESR (OR = 3.05), PDW (OR = 4.67), MPV (OR = 3.5), and P-LCR (OR = 7.67).ConclusionOur study demonstrated clinical laboratory parameters and platelet indices as useful surrogate markers of subclinical inflammation associated with LTBI.

Post-COVID-19 pulmonary fibrosis (post-CPF) has emerged as a serious complication with profound implications for long-term respiratory health. This short review explores the multifactorial mechanisms underlying post-CPF, emphasising the role of oxidative stress, epithelial-to-mesenchymal transition (EMT), and dysregulated immune responses. Key signalling pathways, such as TGF-β, WNT, and Cadherin, are pivotal in fibrosis progression, offering potential therapeutic targets. Biomarkers, such as MUC4, KRT5, and ATP12A show promise for early detection and therapeutic targeting, as they share molecular features with idiopathic pulmonary fibrosis (IPF) and fibrotic interstitial lung diseases (f-ILDs), suggesting opportunities to repurpose antifibrotic therapies. Despite these advancements, significant gaps remain in understanding the cellular and molecular mechanisms underlying fibrosis progression, hindering effective management of post-CPF. Addressing these challenges through a targeted approach is critical to improving outcomes for survivors of severe COVID-19.

With the advancement of combination antiretroviral therapy (ART), over 50% of people with HIV (PWH) in the United States are now over the age of 50. A hallmark of the aging immune system is a progressive dysfunction of both the innate and adaptive immune responses, often characterized by clonal expansion of memory T cells. However, the impact of age-related immune dysfunction on HIV/SIV reservoir dynamics remains understudied. We hypothesized that age-associated clonal expansion of memory T cells contributes to the increase of the HIV reservoirs in older PWH (OPWH). In this retrospective study, we utilized archived peripheral blood mononuclear cells (PBMCs) from young and older PWH with suppressed plasma viremia for at least 5 years and quantified both intact and total HIV proviral DNA from CD4+ T cells. Alongside the human study, we also analyzed samples from SIV-infected, ART-suppressed young and aged rhesus macaques, quantifying intact and total proviruses in CD4+ T cells. We observed a significantly higher level of intact and total proviral DNA in older compared to younger PWH. The frequency of intact provirus was positively correlated with activated CD4+ and CD8+ T cells. Consistently, in the non-human primate model, aged macaques exhibited significantly higher levels of intact and total SIV proviruses in CD4+ T cells than their younger counterparts. Collectively, these findings suggest that the HIV/SIV reservoir expands with age, potentially driven by immune activation. Future studies are warranted to elucidate the mechanisms underlying reservoir expansion in the aging population.

The decline in dengue incidence and/or prevalence during the COVID-19 pandemic (2020- 22) appears to be attributed to reduced treatment-seeking rates, under-reporting, misdiagnosis, disrupted health services and reduced exposure to mosquito vectors due to prevailing lockdowns. There is limited scientific data on dengue virus (DENV) disease during the COVID-19 pandemic. Here, we conducted a community-based, cross-sectional, cluster-randomized survey to assess anti-DENV and anti-SARS-CoV-2 seroprevalence, and also estimated the spatial distribution of DENV-positive aedine mosquito vectors during the COVID19 pandemic across all the 38 districts of Tamil Nadu, India. Using real-time PCR, the prevalence of DENV in mosquito pools during 2021 was analyzed and compared with the previous and following years of vector surveillance, and correlated with anti-DENV IgM and IgG levels in the population. Results implicate that both anti-DENV IgM and IgG seroprevalence and DENV positivity in mosquito pools were reduced across all the districts. A total of 13464 mosquito pools and 5577 human serum samples from 186 clusters were collected. Of these, 3.76% of the mosquito pools were positive for DENV. In the human sera, 4.12% were positive for anti-DENV IgM and 6.4% for anti-DENV IgG. While the anti-SARS-CoV-2 levels significantly correlated with overall DENV seropositivity, COVID-19 vaccination status significantly correlated with anti-DENV IgM levels. The study indicates a profound impact of anti-SARS-CoV-2 levels on DENV-positive mosquito pools and seropositivity. Continuous monitoring of anti-DENV antibody levels, especially with the evolving variants of SARSCoV-2 and the surge in COVID-19 cases will shed light on the distribution, transmission and therapeutic attributes of DENV infection.

Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2 represents unique clinical characteristics. However, their role in altering immunometabolic regulations during acute infection remains convoluted. Here, we evaluated the differential immunopathogenesis of Delta vs. Omicron variants in Golden Syrian hamsters (GSH). The Delta variant resulted in higher virus titers in throat swabs and the lungs and exhibited higher lung damage with immune cell infiltration than the Omicron variant. The gene expression levels of immune mediators and metabolic enzymes, Arg-1 and IDO1 in the Delta-infected lungs were significantly higher compared to Omicron. Further, Delta/Omicron infection perturbed carbohydrates, amino acids, nucleotides, and TCA cycle metabolites and was differentially regulated compared to uninfected lungs. Collectively, our data provide a novel insight into immunometabolic/pathogenic outcomes for Delta vs. Omicron infection in the GSH displaying concordance with COVID-19 patients associated with inflammation and tissue injury during acute infection that offered possible new targets to develop potential therapeutics.