Search Results (98)

Human endogenous retroviruses (HERVs), remnants of ancient germline infections, constitute ~8% of the human genome. Although mostly silenced, these elements can be expressed and play physiological or pathological roles. We investigated HERV expression dynamics, proviral load, and systemic inflammatory status in young and older adults, as well as the impact of regular physical exercise. PBMC and serum samples were collected from 30 young controls (YC), 30 inactive older adults (INAC) and 30 regularly exercising older adults (REG). Expression of HERV-W, -K, -H, Syncytin-1 and -2 was assessed by qPCR using the −2ΔΔCt method, and proviral load (HERV-W, -K, -H) was estimated by relative copy number. Serum cytokines (IL-1β, IL-6, IL-17, TNF-α, IFN-γ, IL-10) were quantified by ELISA. Statistical significance was set at p < 0.05. INAC participants showed higher proviral load of HERV-K, -W and -H compared to YC (p = 0.025), but overall lower HERV expression, except for HERV-K. REG presented increased expression of HERV-W (~1.5-fold, p < 0.0001), HERV-H (~1.8-fold, p < 0.0001; higher than YC p = 0.01), HERV-K (vs. YC p = 0.02) and Syncytin-1 (~1.4-fold vs. INAC and YC, p < 0.01). HERV-K was the most upregulated element in INAC. HERV-W and HERV-H expression were strongly correlated in all groups. INAC showed a pro-inflammatory profile, with elevated IL-6/IL-10, IL-1β/IL-10, and IFN-γ/IL-10 ratios. Older adults exhibit higher HERV proviral load, suggesting possible age-related insertions. Regular physical exercise modulates HERV expression, whereas inactivity is associated with reduced expression and increased inflammation. HERV-W and HERV-H maintain coordinated expression across ages, indicating interplay between inflammatory balance, aging, and retroviral activity. Full article

Human T-cell leukemia virus type-1 (HTLV-1) is endemic to numerous regions worldwide, including Central Australia. The Australo-Melanesian subtype-C is endemic within Australia and Oceania, whereas subtype-A is the most widely distributed subtype globally. The lack of an approved vaccine highlights HTLV-1 as a neglected public health issue. To inform the development of HTLV-1 Envelope (Env)-based vaccines, we assessed anti-Env antibodies in an HTLV-1c+ cohort of First Nations individuals in Central Australia. Of the 62 plasma samples from patients with confirmed HTLV-1 serological diagnosis, 76% were positive for Env binding in ELISA, but 90% neutralized HTLV-1c pseudovirus (PSV) infection. Neutralization breadth with the capability of blocking both subtype-A and subtype-C PSV infection was identified in 100% of samples tested. Proviral load was positively associated with anti-Env response, with binding epitopes mapping to the proline-rich region of gp46-SU. Env-directed IgG showed the capacity to engage Fcγ receptors key to inducing antibody-dependent cellular cytotoxicity/phagocytosis responses. Serological response was not associated with comorbidities linked to HTLV-1c in this population (bronchiectasis, chronic kidney disease, diabetes). These findings demonstrate that potent humoral immunity arises and is sustained during HTLV-1 infection, suggesting that an Env-based vaccine displaying authentically native epitopes will be capable of recapitulating these neutralizing responses. Full article

Background: There is limited information about treatment success and outcomes in retrovirus-positive cats diagnosed with feline infectious peritonitis (FIP). Methods: A survey was distributed to caretakers of cats with feline leukemia virus (FeLV) and/or feline immunodeficiency virus (FIV) that were treated with GS-441524 for presumptive effusive FIP based on survey responses. Results: Cats with FIV developed FIP at an older age and longer after retrovirus infection than cats with FeLV. The average starting dosage (7 mg/kg/d) was increased in 65% of cats, and treatment was extended in 35%. Three cats relapsed (18%). There was a 94% (16/17) twelve-week survival rate and 82% (14/17) one-year survival rate. Seven cats were alive at follow-up, a median of 1306 days (range 983–2069) after FIP diagnosis, but many cats succumbed to neoplasia. Conclusions: Treatment success for retrovirus-positive cats with presumptive FIP was similar to previously reported outcomes for FIP alone. This could support current evidence of successful antiviral therapy for similar populations, if noncurrent, unstandardized protocols and unlicensed product use are considered. Additional studies are needed to determine ideal protocols for rapid resolution of FIP, good long-term survival, and limited relapse in retrovirus-positive cats, and the impact of the FeLV proviral load. Full article

Bovine leukemia virus (BLV) is an oncogenic deltaretrovirus that infects B cells, and its possible presence in humans has garnered increasing attention. This study included 58 participants: 11 with B-cell precursor acute lymphoblastic leukemia (B-ALL, cases) and 47 healthy individuals (controls). Researchers assessed anti-gp51 antibodies and BLV proviral DNA in bone marrow and blood samples. Seropositivity was observed only in the B-ALL group (18.2%; 2/11), while all controls were seronegative. Quantitative PCR targeting the pol gene detected proviral DNA in 74.1% of samples, with similar detection rates between cases and controls. Although proviral load was higher in controls, this difference did not reach statistical significance. Conventional and nested PCR for other viral genes revealed a differential pattern: amplification of the tax gene was significantly associated with B-ALL, whereas gag and env were not. Bayesian Chow–Liu network analyses identified dependencies among viral genes and suggested that contextual factors, such as fieldwork, may influence the association between molecular positivity and B-ALL. Sequence analyses showed that the detected BLV strains clustered with previously reported bovine and human sequences from Colombia, all within genotype 1. These findings support human exposure to BLV and raise important questions about its persistence and potential connections to hematological diseases in humans. Full article

Despite increasing reports of zoonotic simian foamy virus (SFV) infections globally, knowledge of its genetic adaptation in humans and impact on viral transmission and pathogenicity remains limited. We obtained complete SFV genomes using metagenomics analysis of viral isolates from peripheral blood lymphocytes (PBLs) and throat specimens from a worker (Case 6) and source chimpanzee (B1) that bit him. We analyzed viral diversity in three genomic regions (LTR, tas, and bet) involved in replication and latency using longitudinal specimens (PBLs, throat, saliva, urine, and semen) from Case 6 over five years, and PBLs from B1 and five additional chimpanzees over three years. Proviral loads were measured using a validated qPCR assay. Phylogenetic analysis revealed nearly identical SFV genomes in Case 6 and B1. Overall, bet sequences exhibited high genetic stability across body compartments and over time, with evidence of compartmentalization in Case 6 urine and semen specimens. G→A substitutions in GG and GA motifs in bet indicated heterogeneous APOBEC-associated editing across hosts and anatomical compartments following zoonotic transmission. Case 6 had significant deletions in the LTR region that were absent in B1 and other chimpanzees. Length variation in tas, including truncated forms, was observed across longitudinal specimens from Case 6, B1, and other chimpanzees. Proviral loads were consistently low and undetectable in most Case 6 urine specimens. Together, analysis of this SFV transmission pair identifies genomic changes likely to affect viral replication and persistence, highlighting mechanisms that may limit secondary transmission and pathogenicity of SFV in humans. Full article

The family Arenaviridae encompasses zoonotic, rodent-borne pathogens (e.g., Lassa, Machupo, and Junín viruses) that cause severe viral hemorrhagic fevers with high case fatality rates. The current therapeutic landscape is severely limited, underscoring the urgent need for novel antiviral strategies. A promising approach involves combining directly acting antivirals with host-targeted antivirals. A compelling host-targeted antiviral target is the aryl hydrocarbon receptor (AHR). This ubiquitous ligand-activated transcription factor is a recognized pro-viral host factor across multiple viral families. Building on prior work with Junín and Tacaribe viruses, we investigated whether the AHR inhibitor CH223191 could enhance the virus-directed antiviral activity of favipiravir against these viruses. First, we evaluated the toxicity and antiviral potential of CH223191 against a lethal Junín virus infection in male and female hTfR1 mice. After demonstrating substantial protection, we conducted preliminary assays to study the antiviral effects of combining CH223191 and favipiravir on Tacaribe virus (TCRV) infections in the Vero cell culture model. We observed synergistic interaction with all four models (ZIP, Loewe, Bliss, and HSA). We next determined the sub-optimal dose of favipiravir and conducted an antiviral combination study in the AG129 mouse model infected with TCRV. The combination effectively protected mice from a lethal TCRV infection and showed cooperative effects, reducing weight loss and viral loads. Overall, these results show that the AHR is a promising pharmacological target for the development of novel antivirals. Furthermore, we discovered a cooperative interaction between the activities of favipiravir and CH223191. Full article

Bovine leukemia virus (BLV), the most prevalent neoplastic disease of cattle worldwide, is the causative agent of enzootic bovine leukosis. Polymorphisms in the bovine leukocyte antigen (BoLA)-DRB3 gene can influence host immune responses to pathogens, including BLV. However, the associations between specific BoLA-DRB3 alleles, BLV proviral load (PVL), a useful index for estimating disease progression and transmission risk, and BLV infection in Chinese cattle remain unknown. In this study, we identified 28 previously reported alleles in 289 Holstein cattle from Shandong Province, China, using polymerase chain reaction sequence-based typing. We further investigated whether BoLA-DRB3 polymorphisms influenced infection status and identified BoLA-DRB3*011:01 as an allele associated with susceptibility to BLV infection. An association analysis of allele frequencies between cattle with high and low PVL demonstrated that BoLA-DRB3*014:01:01 was significantly associated with low PVL. Farms with a higher frequency of cattle carrying BoLA-DRB3*014:01:01 had lower mean PVL values than farms with a lower frequency, indicating that resistant alleles are linked to low PVL levels. To our knowledge, this is the first study to demonstrate that BoLA-DRB3 polymorphisms associate with differential susceptibility to BLV infection and PVL in Holstein cattle in China. These findings may contribute to BLV control and eradication efforts through genetic selection. Full article

The pathogenesis of koala retrovirus (KoRV) has been explored in various contexts, yet its role in tumorigenesis remains incompletely understood. Unlike acute transforming retroviruses, KoRV lacks a viral oncogene but may contribute to oncogenesis via indirect mechanisms. However, the relationship between KoRV and telomere length, as a potential indicator of telomerase activity, has not been examined. This study investigates the effect of KoRV infection on telomere length in 47 samples from Southern Australian koalas in a novel telomere length quantification method. Telomere lengths of 30 KoRV-negative samples were compared to those of 17 KoRV-positive samples using the Absolute Human Telomere Length Quantification qPCR kit (ScienCell Research Laboratories, California, USA). The telomere length in KoRV-infected WBCs was significantly longer than the uninfected ones (t = −2.059, p-value = 0.045). In line with this, telomere length correlated positively with proviral load (r = 0.421, p-value = 0.003), further linking viral burden to telomere elongation. Furthermore, the effect of age on telomere length differed by infection status (β = −5329.7, p-value = 0.0038); KoRV-positive individuals exhibited longer telomeres at a younger age but experienced more rapid telomere attrition over time compared to KoRV-negative individuals. These results suggest KoRV promotes telomerase elongation ability and modulates age-related telomere dynamics, potentially contributing to subsequent cellular immortality and oncogenesis. These pathways may overlap with other retroviruses, where telomerase dysregulation contributes to their oncogenic potential. This study provides new insights into KoRV pathogenesis and DNA quantification methodology, which could be valuable for future research by identifying predictive markers for tumour progression and potential therapeutic targets in affected koalas. Full article

Bovine leukemia virus (BLV), an oncogenic retrovirus of the genus Deltaretrovirus, causes enzootic bovine leukosis (EBL), the most prevalent neoplastic disease in cattle and a major source of economic loss. While BLV prevalence has been studied in commercial breeds, data on native Latin American cattle remain limited. This study assessed BLV infection and proviral load in 244 animals from six native breeds: Argentine Creole (CrAr), Patagonian Argentine Creole (CrArPat), Pampa Chaqueño Creole (CrPaCh), Bolivian Creole from Cochabamba (CrCoch), Saavedreño Creole (CrSaa), and Siboney (Sib), sampled across Argentina, Bolivia, Paraguay, and Cuba. BLV-CoCoMo-qPCR-2 assay detected BLV provirus in 76 animals (31.1%), with a mean load of 9923 copies per 10⁵ cells (range: 1–79,740). Infection rates varied significantly by breed (9.8% in CrAr to 83.8% in CrPaCh) and country (15.6% in Argentina to 83.8% in Paraguay) (p = 9.999 × 10⁻⁵). Among positives, 57.9% exhibited low proviral load (≤1000 copies), and 13.2% showed moderate levels (1001–9999), suggesting potential resistance to EBL progression. This is the first comprehensive report of BLV proviral load in Creole cattle across Latin America, offering novel epidemiological insights and highlighting the importance of native breeds in BLV surveillance. Full article

Coronaviruses, including avian infectious bronchitis virus (IBV), utilize host cellular pathways to evade the host immune response. The aryl hydrocarbon receptor (AhR), a key antiviral regulator exploited by mammalian coronaviruses like SARS-CoV-2, remains unclear in avian coronavirus pathogenesis. This study examined AhR’s involvement during IBV infection using H1299 and Vero cells with pharmacological modulation (AhR antagonist CH223191/agonist kynurenine) and shRNA-mediated silencing. Viral replication was quantified through plaque assays, qRT-PCR, and Western blot. The results reveal IBV-induced AhR activation, driving downstream CYP1A1 expression and pro-inflammatory cytokine production. CH223191 treatment reduced IBV titers, RNA loads, and N protein expression dose-dependently, while kynurenine showed no effect. AhR knockdown similarly reduced N protein expression, confirming its proviral role. An IBV-encoded noncoding RNA was identified as a modulator of AhR activation, suggesting viral balancing of immune evasion and replication efficiency. These results establish AhR as a conserved host factor co-opted by IBV, and highlight AhR antagonism as a promising therapeutic strategy. By bridging insights from avian and mammalian coronaviruses, this work informs strategies to address IBV’s genetic variability and supports development of broad-spectrum antiviral therapies. Full article

Human T-cell leukemia virus type 1 (HTLV-1) establishes lifelong infection and is associated with severe diseases such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cytotoxic T lymphocytes (CTLs), especially those specific for the viral protein Tax, play a pivotal role in controlling HTLV-1 infection. However, conventional humanized mouse models fail to fully reconstitute human immune responses, limiting their utility for evaluating CTL-mediated immunity. This study aimed to establish a physiologically relevant in vivo model to investigate human CTL responses against HTLV-1. To achieve this, we utilized NOG-HLA-A02 transgenic (Tg) mice expressing human HLA-A02:01 on thymic epithelial cells, enabling proper development of HLA-restricted human T cells. Compared to conventional humanized NOG mice, HTLV-1-infected humanized NOG-HLA-A02 Tg mice exhibited significantly reduced HTLV-1 proviral load (PVL), decreased expansion of infected CD4⁺ T cells, a trend toward increased frequencies of Tax-specific CD8⁺ T cells, and prolonged survival. These results demonstrate that the expression of HLA-A02:01 facilitates robust CTL-mediated immune control of HTLV-1. This model provides a powerful platform for dissecting HTLV-1 immunopathogenesis and evaluating CTL-targeted therapeutic strategies, including vaccines and immune checkpoint inhibitors. Full article

The dynamics of the HIV reservoir during antiretroviral therapy (ART) exhibit variability, with a pronounced decline during the initial years of treatment. However, the identification of biomarkers and host factors associated with the decay of the different forms of HIV proviruses remains to be fully elucidated. We conducted a longitudinal study on people with HIV provided by the Spanish National HIV cohort. We assessed the HIV-DNA levels by Intact Proviral DNA Assay, and inflammatory markers using the Proximity Extension Assay, before and after ART initiation. A multivariate linear regression model was employed to identify potential predictive markers. Our results highlight the identification of novel inflammatory markers, such as ADA, DNER, CDCP1, SCF, among others, that varied significantly over ART initiation. In addition, we observed several markers associated with intact HIV-DNA before ART initiation (CD8A, CX3CL1, and ST1A1) or during undetectable viral load post-ART (IL-10). Moreover, up to five markers were able to predict the intact HIV reservoir decay over ART. The strongest predictor was Stem Cell Factor (SCF), where higher baseline levels of this marker were associated with a greater decline in the intact HIV reservoir. In conclusion, we have identified inflammatory markers associated with the size and dynamics of the HIV-DNA reservoir. These findings provide new insights that could contribute to the development of multi-targeted intervention strategies aimed at modulating or monitoring the HIV reservoir size. Full article

Bovine leukemia virus (BLV) infects B cells in ruminants and causes lymphoma after an extended latency period. Previous studies have demonstrated T-cell exhaustion through the upregulation of immunoinhibitory molecules, including programmed death-ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-3 (TIM-3), in BLV-infected cattle. However, studying T-cell exhaustion across all BLV infection stages remains challenging due to the virus’s prolonged latency in cattle. Sheep provide a valuable model, as they develop lymphoma more rapidly than cattle. This study examined PD-L1 and TIM-3 expression kinetics and T-cell function in BLV-infected sheep. During persistent infection, PD-L1 expression was correlated with BLV proviral load. TIM-3 expression increased in CD4⁺, CD8⁺, and γδTCR⁺ T cells. Functional analysis revealed that TIM-3 blockade enhanced T-cell activation markers (CD25 and CD69) in cultured PBMCs from infected sheep and increased CD69⁺IFN-γ⁺ and CD69⁺TNF-α⁺ populations, particularly among CD4⁺ T cells. Combined PD-L1 and TIM-3 blockade significantly enhanced cytokine production in both CD4⁺ and CD8⁺ T cells, while PD-L1 blockade alone showed limited effects. These findings demonstrate the effect of TIM-3 blockade in restoring immune function during chronic BLV infection, effective both alone and in combination. This study validates sheep as a valuable model for investigating immune checkpoint dynamics and evaluating immunotherapies for BLV infection and other chronic diseases. Full article

Bovine leukemia virus (BLV) is widespread globally and causes economic losses in the cattle industry. BoLA-DRB3 is a polymorphic gene associated with the BLV proviral load (PVL), which correlates with disease progression and transmission risk. However, the distribution of BoLA-DRB3 alleles in semen and their potential impact on the PVL of progeny remain unclear. Here, we investigated whether BLV susceptibility linked to BoLA-DRB3 alleles in semen is inherited by progeny. We analyzed 178 commercial semen samples from Japanese Black sires and identified 20 BoLA-DRB3 alleles and 70 genotypes. The susceptible allele DRB3*016:01 was the most frequent (26.4%), whereas resistant alleles DRB3*011:01 (5.3%) and DRB3*009:02 (0.6%) were rare. Subsequently, we collected blood samples from 200 progeny produced by artificial insemination using 36 of the 178 semen samples. Progeny derived from semen carrying at least one susceptible allele and no resistant alleles had significantly higher PVL in the blood than those derived from semen containing at least one resistant allele. These findings demonstrate that BLV susceptibility is inherited via BoLA-DRB3 alleles in semen and highlight the potential of BoLA-DRB3 alleles as valuable markers in breeding strategies aimed at mitigating BLV infection and transmission. Full article

Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation. Full article