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PubMed2025

Placental CCR5 polymorphisms in relation to fetal growth.

The placenta mediates fetal growth, and its development and function are influenced by immune interactions at the maternal-fetal interface. The cysteine-cysteine chemotactic cytokine receptor type 5 (CCR5) gene codes for a pro-inflammatory protein receptor expressed in the placenta on syncytiotrophoblasts and Hofbauer cells. Associations of the placental-fetal genotype at CCR5 and birth outcomes have not been examined. Furthermore, influence of CCR5 polymorphisms on nearby DNA methylation in the placenta and in the context of infection is understudied. We assessed two functional polymorphisms in CCR5, a 32 base pair deletion (Δ32) in the open reading frame and an A/G promoter point mutation (rs1799987) in EPIC (n = 233) a cohort consisting of complicated and uncomplicated pregnancies ascertained in Vancouver BC and found that the variant alleles were associated with birth weight (p = 0.007 and p = 0.01 respectively). We validated the association of rs1799987 with birthweight (p = 0.003) in the published NICHD dataset of normative term births (n = 286). These variant associations were, however, not present in CARMA-Preg (n = 200) a cohort enriched for HIV-exposure. Interestingly, we found rs1799987 was associated with altered DNA methylation (DNAme) at multiple CpGs spanning over 275 kb, overlapping both the CCR2 and CCR5 genes. DNAme in this region was, however, not associated with birthweight. Further investigations are needed to validate the association of CCR5 variants with fetal growth. Such studies must consider the population structure and demographics, as well as the large haplotype blocks spanning this region, which make it difficult to assign a causal relationship to specific variants.

Humans↗

PubMed2025

Enhanced cleavage of genomic CCR5 using CASX2Max.

Development of novel CRISPR/Cas systems enhances opportunities for gene editing to treat infectious diseases, cancer, and genetic disorders. CasX2 (PlmCas12e) belongs to the class II CRISPR system derived from Planctomycetes, a non-pathogenic bacterium present in aquatic and terrestrial soils and offers several advantages as a potential therapeutic CRISPR system over Streptococcus pyogenes Cas9 (SpCas9) and Staphylococcus aureus Cas9 (SaCas9). These advantages include its smaller size, distinct protospacer adjacent motif (PAM) requirements, staggered cleavage cuts that promote homology-directed repair, and the absence of pre-existing immunity in humans. We compared the cleavage efficiency and double-stranded break repair characteristics between CasX2 and CasX2Max, a recently generated CasX2 variant with three amino acid substitutions, for targeting CCR5, a gene that encodes the CCR5 receptor important for HIV-1 infection. Two single guide RNAs (sgRNAs) were designed that flank the 32 bases deleted in the natural CCR5 ∆32 mutation. Nanopore sequencing demonstrated that CasX2 using sgRNAs with spacers of 17 nucleotides (nt), 20 nt or 23 nt in length were ineffective at cleaving genomic CCR5. In contrast, CasX2Max using sgRNAs with 20 nt and 23 nt spacer lengths, enabled cleavage of genomic CCR5. Structural modelling indicated that two of the CasX2Max amino acid substitutions enhanced sgRNA-DNA duplex stability, while the third improved DNA strand alignment within the catalytic site. These structural changes likely underlie the increased activity of CasX2Max in cellular gene excision. In sum, CasX2Max consistently outperformed native CasX2 across all assays and represents a superior gene-editing platform for therapeutic applications.

Humans↗

PubMed2026

Maraviroc alleviates neuropathic pain symptoms in a mouse model of spared nerve injury.

Chronic pain represents a major health problem in the health care system. According to the CDC data brief in 2020, 20.4% of adults have chronic pain. There has been no promising therapy for chronic pain. Currently available treatments include medications such as nonsteroidal anti-inflammatory drugs, antiepileptic drugs, tricyclic antidepressants, corticosteroids, opioids, and cannabinoids, all of which may cause various negative side effects. Thus, there is an urgent need to develop novel, efficacious, and safe interventions for treating pain. Studies have shown that proinflammatory cytokines and chemokines make important contributions to the initiation and persistence of pain. We have found that C-C motif chemokine ligand 5 levels increased at day 14 post-spared nerve injury (SNI). This study was designed to investigate the effect of maraviroc (MVC), an FDA-approved CCR5 antagonist, on neuropathic pain in a mouse model of SNI. We found that MVC alleviated SNI-induced mechanical allodynia at 3, 7, and 14 days postinjury. MVC treatment also prevented SNI-mediated thermal hypersensitivity at 7 and 14 days postinjury in both male and female cohorts. SNI resulted in weight-bearing deficits, which were corrected by MVC administration in male mice. RNA sequencing analysis revealed that MVC rescued SNI-induced dysregulation of sex-specific canonical pathways in the spinal cord. Collectively, our findings showed that MVC could reduce neuropathic pain following peripheral nerve injury, providing a base for the repurposing of this FDA-approved human immunodeficiency virus drug as a pain reducer in clinical applications. SIGNIFICANCE STATEMENT: Spared nerve injury-induced neuropathic pain is associated with upregulation of the C-C motif chemokine ligand 5. Targeting the C-C motif chemokine ligand 5-CCR5 axis with FDA-approved maraviroc alleviated pain phenotype through modulating different pathways in male and female mice.

Animals↗

PubMed1990

Cadmium-induced multistep transformation of cultured Indian muntjac skin fibroblasts.

During the past five years we have made a series of cadmium-transformed and resistant fibroblast cell lines by continuous low-level exposure to cadmium. In the present paper we describe the use of four of these lines with varying degrees of transformation to investigate the multistep nature of cadmium carcinogenesis. These include: (a) M cell, an immortal but nontransformed muntjac skin fibroblast line; (b) CCR5, a morphologically transformed and cadmium-resistant line derived from M cells after 20-months continuous exposure to small step-wise increases in cadmium; (c) SCR5, a tumorigenic line derived by selection (in the absence of cadmium) of rapidly growing CCR5 agar colonies; (d) T1, a line derived from an SCR5 tumour growing in a nude mouse. We have compared the morphological characteristics of the four cell lines using light and electron microscopy and evaluated their ability to grow in liquid culture, soft agar and nude mice. We have also examined the changes which have occurred in their cytoskeletons and extracellular matrices using fluorescent antibodies to actin, tubulin and fibronectin and related these to the strength of their cell-cell and cell-substrate attachments and to their levels of transformation and tumorigenesis. We have shown that, while some changes occur in a single step (e.g. intracellular cytoskeletal changes), others are gradual (e.g. changes in extracellular matrix, focus formation and ability to grow in soft agar). We conclude that continuous exposure to low levels of cadmium can initiate growth and structural changes which subsequently lead to cell transformation and tumorigenesis on the removal of cadmium. Though change with cadmium was slow, many of the transformed characteristics are similar to those reported for viral and chemically transformed cells.

Actins↗

PubMed2026

Near Full-Length Genome Characterization of a Novel Second-Generation HIV-1 CRF01_AE/CRF07_BC Recombinant Identified in an MSM Individual in Guizhou, China.

The cocirculation of CRF01_AE and CRF07_BC among men who have sex with men (MSM) in China may facilitate the emergence of genetically complex HIV-1 recombinants. Here, we identified and characterized a novel second-generation HIV-1 CRF01_AE/CRF07_BC recombinant, designated GY0192, from a 25-year-old MSM individual in Guiyang, Guizhou Province, southwest China, using near full-length genome (NFLG) analysis. Recombination analyses identified four breakpoints at HXB2 positions 3,125, 5,687, 6,375, and 9,176, generating a distinct five-segment mosaic genome. Subregion phylogenetic analyses showed that the two CRF01_AE-derived fragments clustered with the CRF01_AE cluster 5 lineage, while all three CRF07_BC-derived fragments grouped with CRF07_BC lineages frequently circulating among MSM in China, indicating that both parental components of GY0192 were phylogenetically related to lineages frequently reported among MSM populations in China. The virus was also predicted to be CCR5-tropic, adding epidemiological relevance because CCR5-tropic viruses are commonly involved in transmission and early infection. Together, these findings identify GY0192 as a distinct CRF01_AE/CRF07_BC mosaic and suggest that cocirculating MSM-associated HIV-1 lineages may provide opportunities for interlineage recombination. This case expands the known spectrum of CRF01_AE/CRF07_BC recombinants in Guizhou and underscores the value of NFLG-based surveillance for detecting underrecognized HIV-1 genetic complexity in southwest China.

Humans↗

PubMed2026

Whole-exome characterization of host genetic variation in HIV-associated genes across the high-prevalence Mizo population, Northeast India.

BACKGROUND: The Mizoram state of Northeast India has one of the highest HIV prevalence rates in Asia, yet the host genetic factors influencing HIV susceptibility in this Tibeto-Burman population remain uncharacterised. METHODS: We performed whole-exome sequencing using Illumina NovaSeq 6000, mean coverage 100X on 76 HIV-negative Mizo individuals. Variants were called using GATK HaplotypeCaller v4.3 against GRCh38p14, annotated with ANNOVAR, and filtered using hard-quality thresholds (QD ≥ 2, SOR ≤ 3, MQ ≥ 40, DP ≥ 10, GQ ≥ 20). The allele frequencies were compared against gnomAD v2.1.1 population databases. Hardy-Weinberg equilibrium was assessed using the Wigginton exact test with Bonferroni correction. RESULTS: Post-quality filtering resulted in 12,011 sample-variants across 2,821 unique positions from 36 HIV-associated loci (33 protein-coding genes, 2 chemokine ligands, and 3 lncRNA targets). Of these, 784 observations (51 unique positions) were high-impact nonsynonymous or loss-of-function variants. ADAR rs2229857 (p.K384R, NM_015840) was the most frequently observed variant (Mizo carrier frequency = 0.895; 95% CI: 0.806-0.946). CXCR1 rs16858808 (p.R335C) showed the greatest population enrichment (Mizo carrier frequency = 0.197; 95% CI: 0.123-0.300; 7.65-fold carrier-frequency enrichment versus gnomAD South Asian; CADD = 15.60). Sixteen of 20 tested variants deviated from Hardy-Weinberg equilibrium after Bonferroni correction (p < 0.0025), predominantly showing excess homozygosity consistent with the endogamous Mizo population. The protective variant CCR5-Δ32 was absent in all the 76 individuals tested. CONCLUSION: This first whole-exome characterization of HIV host genes in the Mizo population identifies CXCR1 rs16858808 as the most population-enriched functional variant and reveals a pervasive endogamy signature. These findings provide a population-specific genetic framework for future HIV susceptibility studies and ART pharmacogenomics research.

Humans↗

PubMed2025

DNA methylation and multi-omics profiling of T cells uncovers chemotactic pathways and proliferation-linked hypomethylation in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a loss of orexin-producing cells in the brain and involves autoimmune mechanisms, including the presence of autoreactive T cells. In this study, we performed genome-wide DNA methylation analysis using both CD4+/CD8+ T cells from 42 NT1 patients and 42 controls across discovery and replication cohorts. To identify methylation changes more robustly associated with the disease, we prioritized differentially methylated regions (DMRs) over single-site differentially methylated positions (DMPs). Furthermore, to validate and interpret DMP-level associations, we integrated genome-wide genotype and gene expression data obtained from the same individuals. As a result, the DMR analysis identified 15 reproducible DMRs in CD4+ T cells and 5 in CD8+ T cells, with most DMRs shared between the two cell types. Shared DMRs included regions associated with CCL5 (p = 2.1E-02) and CCR4 (p = 8.3E-03). Integrative analysis with genotype and gene expression data also showed that the DMP related to S100A4, which promotes lymphocyte migration through CCR5 and CXCR3 receptors, was associated with the disease in CD4+ T cells. Pathway analysis of genes identified through both the DMR and integrative analyses indicated enrichment in cell chemotaxis-related pathways, suggesting that aberrant chemokine-mediated cell migration plays a central role in NT1 pathogenesis. Further, NT1-associated methylation changes were predominantly hypomethylation events, significantly enriched in non-promoter, non-CpG island regions (p = 1.74E-102). We further observed that global hypomethylation levels were correlated with hypoSC, a mitotic index estimated from methylation data, highlighting increased T cell proliferation in NT1.

Humans↗