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PubMed2000

Induction of antibodies in guinea pigs and rhesus monkeys against the human immunodeficiency virus type 1 envelope: neutralization of nonpathogenic and pathogenic primary isolate simian/human immunodeficiency virus strains.

We have compared the abilities of human immunodeficiency virus type 1 (HIV-1) envelope V3 peptides and recombinant gp120 to induce antibodies that neutralize simian/human immunodeficiency viruses (SHIVs). SHIV-89.6 is a nonpathogenic SHIV that expresses the envelope protein of primary HIV-1 isolate 89.6. SHIV-89.6P, clone KB9, is a pathogenic SHIV variant derived from SHIV-89.6. Infection of rhesus monkeys with these SHIVs rarely induces anti-V3 region antibodies. To determine the availability of the gp120 V3 loop for neutralizing antibody binding on SHIV-89.6 and KB9 virions, we have constructed immunogenic C4-V3 peptides from these SHIVs and induced anti-V3 antibodies in guinea pigs and rhesus monkeys. We found that both SHIV-89.6 and KB9 C4-V3 peptides induced antibodies that neutralized SHIV-89.6 but that only SHIV-KB9 C4-V3 peptide induced antibodies that neutralized SHIV-KB9. Immunoprecipitation assays demonstrated that SHIV-KB9 C4-V3 peptide-induced antibodies had a greater ability to bind SHIV-KB9 envelope proteins than did antibodies raised against SHIV-89.6 C4-V3 peptide. We have used a series of mutant HIV-1 envelope constructs to map the gp120 determinants that affect neutralization by anti-V3 antibodies. The residue change at position 305 of arginine (in SHIV-89.6) to glutamic acid (in SHIV-KB9) played a central role in determining the ability of peptide-induced anti-V3 antiserum to neutralize primary isolate SHIVs. Moreover, residue changes in the SHIV-89.6 V1/V2 loops also played roles in regulating the availability of the V3 neutralizing epitope on SHIV-89.6 and -KB9. Thus, SHIV-89.6 and -KB9 V3 region peptides are capable of inducing neutralizing antibodies against these primary isolate SHIVs, although the pathogenic SHIV-KB9 is less easily neutralized than its nonpathogenic variant SHIV-89.6. In contrast to natural infection with SHIV-89.6, in which few animals make anti-V3 antibodies, C4-V3 peptides frequently induced anti-V3 antibodies that neutralized primary isolate SHIV strains.

Amino Acid Sequence↗
PubMed2026

STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons.

BACKGROUND: Variants in STX1B/syntaxin-1B are linked to a spectrum of fever-associated epilepsy syndromes. While studies in murine models have provided mechanistic insights, their relevance to human disease in a heterozygous context may be limited. METHODS: We investigated two pathogenic STX1B variants using isolated single neurons and neuronal network cultures derived from patient-specific induced pluripotent stem cells. These carried either a de novo p.G226R variant, associated with severe developmental epilepsy, or an InDel variant (p.K45delinsRCMIE/p.L46M) linked to a transient familial seizure syndrome. Synaptic function and network excitability were assessed using patch-clamp and multi-electrode array recordings, alongside morphological and transcriptomic profiling. FINDINGS: G226R exhibited both gain- and loss-of-function characteristics, with increased miniature excitatory postsynaptic current frequency in networks but not in autapses, and synaptic failure during sustained high-frequency stimulation. For the InDel variant, the predicted loss-of-function phenotype based on reduced syntaxin-1B levels was not detectable at the single-cell level, likely masked by compensatory synaptic upregulation. At the network level, however, both variants were associated with neuronal hyperexcitability, characterised by more frequent and prolonged bursting activity, with a much stronger phenotype in G226R-containing networks. Transcriptomic profiling revealed a differential dysregulation of synaptic and other neuronal genes. INTERPRETATION: The divergence between morphological, electrophysiological and transcriptomic findings suggests that compensatory mechanisms may contribute to network hyperexcitability. Initially engaged to maintain homoeostasis, they may ultimately contribute to a pathological network state. The graded severity of network alterations across STX1B variants correlates with the clinical phenotypes. FUNDING: BMBF (Treat ION-01GM2210A, SNAREopathies-01EW1809A), 2023 FEBS Summer Fellowship, Fortüne programme (2610-0-0), EKFS college precise.net, Open Access Publishing Fund of University of Tübingen.

Humans↗
PubMed2026

[Analysis of clinical phenotypes and pathogenicity of a c.4476+5G>T variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus].

OBJECTIVE: To explore the pathogenicity and characteristics of a heterozygous splicing variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus (GEFS+). METHODS: A retrospective analysis was carried out on the clinical data and results of genetic testing of a GEFS+ pedigree consisting of 5 members who had visited the First Affiliated Hospital of Zhengzhou University on July 1, 2024. Pathogenicity of the splicing variant of the SCN1A gene was validated with a minigene splicing assay. This study was approved by the Medical Ethics Committee of the the First Affiliated Hospital of Zhengzhou University (Ethics No.: KS-2018-KY-36). RESULTS: The proband, a 24-year-old female, presented with FS in conjunct with focal seizures, and both of her younger brothers had Dravet syndrome. All of the three patients had carried a c.4476+5G>T variant of the SCN1A gene, which was unreported previously. Minigene experiment verified that the variant could cause loss of the first 7 bps of exon 24 and 138 bps from exon 23 of the SCN1A gene, resulting in alteration p.V1447_1495delfs*6 and affecting splicing. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.4476+5G>T variant at an intronic site of the SCN1A gene probably underlay the pathogenesis of GEFS+ in this pedigree.

Adult↗
PubMed2026

Expanding the TBL1XR1 Disease Spectrum: Generalized Dystonia Associated with a New Genetic Variant.

BACKGROUND: A growing number of identified genes increasingly reveal genetic overlaps between neurodevelopmental disorders and combined dystonia syndromes. CASE REPORT: We report a 61-year-old man with a neurodevelopmental disorder, mild ataxic signs and generalized dystonia who had been misdiagnosed with cerebral palsy for 40 years. Whole-exome sequencing identified a novel heterozygous pathogenic frameshift variant in TBL1XR1. DISCUSSION: TBL1XR1 variants are classically associated with Pierpont syndrome and autism spectrum disorder. Although movement disorders have been reported, this case suggests generalized dystonia as a possible additional manifestation. It highlights the value of retrospective genetic phenotyping and next-generation sequencing in adults with long-standing neurodevelopmental diagnoses.

Humans↗
PubMed1995

Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease.

The role that transthyretin (TTR) mutations play in the amyloid disease familial amyloid polyneuropathy (FAP) has been probed by comparing the biophysical properties of several TTR variants as a function of pH. We have previously demonstrated that the partial acid denaturation of TTR is sufficient to effect amyloid fibril formation by self-assembly of a denaturation intermediate which appears to be monomeric. Earlier studies on the most pathogenic FAP variant known, Leu-55-Pro, revealed that this variant is much less stable toward acid denaturation than wild-type TTR, apparently explaining why this variant can form amyloid fibrils under mildly acidic conditions where wild-type TTR remains nonamyloidogenic. The hypothesis that FAP mutations destabilize the TTR tetramer in favor of a monomeric amyloidogenic intermediate under lysosomal (acidic) conditions is further supported by the data described here. We compare the acid stability and amyloidogenicity of the most prevalent FAP variant, Val-30-Met, along with the double mutant, Val-30-Met/Thr-119-Met, which serves to model the effects of these mutations in heterozygous patients where the mutations are in different subunits. In addition, we have characterized the Thr-119-Met TTR variant, which is a common nonpathogenic variant in the Portuguese population, to further investigate the role that this mutation plays in protecting individuals who also carry the Val-30-Met mutation against the classically severe FAP pathology. This biophysical study demonstrates that Val-30-Met TTR is significantly less stable toward acid denaturation and more amyloidogenic than wild-type TTR, which in turn is less stable and more amyloidogenic than Thr-119-Met TTR. Interestingly, the double mutant Val-30-Met/Thr-119-Met is very similar to wild-type TTR in terms of its stability toward acid denaturation and its amyloidogenicity. The data suggest that the Thr-119-Met mutation confers decreased amyloidogenicity by stabilizing tetrameric TTR toward acid denaturation. In addition, fluorescence studies monitoring the acid-mediated denaturation pathways of several TTR variants reveal that the majority exhibit a plateau in the relative fluorescence intensity over the amyloid-forming pH range, i.e., ca. pH 4.3-3.3. This intensity plateau suggests that the amyloidogenic intermediate(s) is (are) being observed over this pH range. The Thr-119-Met variant does not exhibit this plateau presumably because the amyloidogenic intermediate(s) do(es) not build up in concentration in this variant. The intermediate is undoubtedly forming in the Thr-119-Met variant, as it will form amyloid fibrils at high concentrations; however, the intermediate is only present at a low steady-state concentration which makes it difficult to detect.

Amino Acid Sequence↗
PubMed2001

Mutations in the X-linked RP2 gene cause intracellular misrouting and loss of the protein.

Mutations in RP2 cause the second most frequent form of X-linked retinitis pigmentosa, a severe retinal degeneration that leads to loss of visual acuity and blindness. The RP2 gene encodes a protein with homology to cofactor C, a tubulin-folding chaperone. By searching protein sequence databases, we identified a whole set of similar molecules from diverse organisms. Protein sequence alignments show that RP2 and cofactor C represent members of two distinct orthologous groups. All previously identified missense mutations affect amino acid residues which are conserved in all RP2 orthologues or both orthologous groups. Intracellular localization of the wild-type protein and mutated variants was determined by fluorescence microscopy of cells expressing RP2 with a green fluorescent protein tag. A mutation in the N-terminus of RP2 abolishes localization to the plasma membrane in HeLa cells. C-terminal protein truncation mutations, which account for 2/3 of the pathogenic RP2 variants, lead to scattered fluorescent foci in the cytoplasm of COS-7 and HeLa cells. Analysis of protein extracts from the respective cells with anti-RP2 antibodies identified truncated proteins of expected size in a low-speed centrifugation pellet while the wild-type protein appeared in the supernatant. Moreover, no protein was detected in immortalized cell lines from patients with protein truncation mutations while mRNA was still present. Thus, loss of the protein and/or aberrant intracellular distribution might be the basis for the photoreceptor cell degeneration in most RP2 cases.

Amino Acid Sequence↗
PubMed2026

Genetic Testing Unveils a Novel Thrombospondin-1 Domain Containing Protein 1 Gene Variant as the Cause of Chronic Edema in a 79-Year-Old Woman.

Edema requires management tailored to its underlying etiology; however, in some cases the cause remains elusive. We describe a 79-year-old woman with lifelong unexplained peripheral edema. Comprehensive evaluation excluded common etiologies such as heart failure, renal dysfunction, and venous thrombosis. Whole-genome sequencing identified a novel homozygous splice-site variant (NM_018676.4:c.58+2T>G) in the thrombospondin-1 domain-containing protein 1 (THSD1) gene, which has previously been associated with non-immune hydrops fetalis (NIHF). This report describes, to our knowledge, the first elderly patient with chronic peripheral edema harboring a likely pathogenic THSD1 variant, suggesting that THSD1-related disease may, in rare instances, persist beyond the perinatal period and present into late adulthood. Although causality cannot be established definitively from a single case, the findings highlight the potential utility of genetic testing in adults with chronic unexplained edema.

chronic edema↗
PubMed2026

[Genetic and functional characterization of a novel KIT splicing variant in a Chinese three-generation pedigree with piebaldism].

OBJECTIVES: To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS: Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS: A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS: The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.

Genetics diagnosis↗
PubMed2024

A novel variant in the SPTB gene underlying hereditary spherocytosis and a literature review of previous variants.

BACKGROUND: Hereditary spherocytosis (HS, MIM#612641) is one of the most common hereditary hemolytic disorders. This study aimed to confirm a novel variant's pathogenicity and reveal a patient's genetic etiology. METHODS: The clinical data of a patient with HS who underwent genetic sequencing at the Children's Hospital of Chongqing Medical University were reviewed retrospectively. In silico prediction and in vitro minigene splicing reporter system were then conducted on the detected variant to analyze its intramolecular impact. A summary of the literature related to HS due to SPTB gene variants was also presented. RESULTS: A novel variant (c.301-2 A > G) in the SPTB gene (NM_001024858.4) was identified in the proband. Using Sanger sequencing, we conclusively confirmed that the inheritance of the variant could not be traced to the biological parents. The in vitro minigene assay revealed three different transcripts derived from the c.301-2 A > G variant: r.301_474del, r.301_306delCCAAAG, and r.301-1_301-57ins. Through a literature review, patients with HS who had been genotypically validated were summarized and the SPTB gene variant profile was mapped. CONCLUSION: We identified a splicing variant of the SPTB gene, thus confirming its aberrant translation. The novel variant was the probable genetic etiology of the proband with HS. Our findings expanded the variant spectrum of the SPTB gene, thus improving the understanding of the associated hereditary hemolytic disorders from a clinical and molecular perspective and contributing to the foundation of genetic counseling and diagnosis.

Humans↗
PubMed2000

Sequence variation within the RPGR gene: evidence for a founder complex allele.

In our study of sequence variation within the RPGR gene associated with X-linked retinitis pigmentosa, we and others have observed a high rate of new mutation within this gene, as all reported mutations are unique or uncommon. In this article we report the identification in a single family of a complex allele of 7 sequence variants in linkage disequilibrium, of which four result in amino-acid alterations (Arg425Lys, DGlu, Thr533Met and Gly566Glu). This complex allele was initially found in a family with XLRP. However, further study revealed an estimated prevalence of 4.3% (15/344 chromosomes) with this complex allele in the European population indicating the non-pathogenic nature of this allele and, along with previously reported polymorphisms, further supporting a high level of human protein diversity for RPGR. This common complex allele may have been established in the population as a founder effect. Complete gene sequencing identified a potential pathogenic sequence variant in the family described (IVS6+5G>A). This study emphasises the need to create a more complete picture of the allelic variation within a gene, suggests cautious interpretation of a phenotypic association with variant sequences, and highlights the potential problems associated with interpreting genetic studies for diagnostic purposes.

Alleles↗
PubMed2001

Structural and functional analysis of a new desmin variant causing desmin-related myopathy.

Desmin-related myopathy is a familial or sporadic disease characterized by skeletal muscle weakness and cardiomyopathy as well as the presence of intracytoplasmic aggregates of desmin-reactive material in the muscle cells. Previously, two kinds of deletions and eight missense mutations have been identified in the desmin gene and proven to be responsible for the disorder. The present study was conducted to determine structural and functional defects in a pathogenic desmin variant that caused a disabling disorder in an isolated case presenting with distal and proximal limb muscle weakness and cardiomyopathy. We identified a novel heterozygous Q389P desmin mutation located at the C-terminal part of the rod domain as the causative mutation in this case. Transfection of desmin cDNA containing the patient's mutation into C2.7, MCF7, and SW13 cells demonstrated that the Q389P mutant is incapable of constructing a functional intermediate filament network and has a dominant negative effect on filament formation. We conclude that Q389P mutation is the molecular event leading to the development of desmin-related myopathy.

Adult↗
PubMed2026

Mechanisms underlying disease-causing variants in promoters and enhancers.

The study of human monogenic disorders has been a powerful tool for generating a deep understanding of protein function/dysfunction and for uncovering underlying biological mechanisms. Here we explore the insights that an expanding catalog of noncoding monogenic disease variants can provide into the functions of the noncoding genome. We focus on small genetic alterations (one to a few tens of base pairs) in cis-regulatory elements-promoters, enhancers and silencers-and their potential mechanisms of action, such as loss or gain of function. We discuss the challenges in determining pathogenicity for variants in the noncoding genome, discuss why there might be so few concrete examples and highlight the opportunities for advancing this area of human genetics by using experimental and machine-learning tools.

Journal Article↗
PubMed2024

Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly.

BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

Humans↗
PubMed2026

When Neurodevelopment Meets Autoimmunity: Pemphigus Foliaceus in Rett Syndrome Expands the Clinical Spectrum-A Case Report.

Rett syndrome (RTT, OMIM 312750) is a complex multisystem neurodevelopmental disorder. Evidence suggests that RTT may have an autoimmune component and inflammatory activation. However, the autoimmune manifestations remain poorly described. Pemphigus foliaceus is a debilitating autoimmune blistering condition caused by IgG autoantibodies that target desmoglein-1 (Dsg1), resulting in widespread skin blistering and lesions. We report a case of pemphigus foliaceus in a 20-year-old female with RTT and discuss its clinical implications. Clinical data obtained from electronic health records were extracted and reviewed. Genetic testing was performed to identify the specific methyl-CpG-binding protein 2 (MECP2) mutation and on an expanded panel of 55 genes associated with pemphigus foliaceus and related blistering disorders. The individual had pemphigus foliaceus, which required immunosuppression, intravenous immunoglobulin (IVIg) therapy, and Rituximab. The disease trajectory was complicated by infections, aspiration pneumonia, and hypoxic cardiac arrest. There was progressive functional decline, and disease control was difficult to achieve, with frequent flares. Genetic testing confirmed a heterozygous pathogenic MECP2 variant (NM_001110792.1:c.952C>T; p.(Arg318Cys)). HLA genotyping identified alleles consistent with the HLA-DRB1*04:02-HLA-DQA1*03:01-HLA-DQB1*03:02 (DR4/DQ8) haplotype. Furthermore, genetic analysis identified a heterozygous DSG1 variant rs12967407. This study reports the first case of pemphigus foliaceus in RTT, expanding the clinical spectrum of RTT beyond its neurodevelopmental phenotype. The DR4/DQ8 haplotype, previously associated with pemphigus susceptibility, supports a background of genetic susceptibility in this individual. No causal association between RTT and pemphigus foliaceus can be inferred from this single case. Rather, this case demonstrates that a rare autoimmune disorder such as pemphigus foliaceus can co-occur with a pathogenic MECP2 mutation. The coexistence of a genetic and autoimmune disease can result in a more complex clinical presentation and treatment course. The case further emphasises the need for increased vigilance in identifying new and emerging systemic pathology alongside RTT.

Humans↗
PubMed2000

[Modification of method of detection virulent Yersinia using crystal violet].

A modified crystal violet method and common agarose medium are proposed for culturing Yersinia before staining. The dish variant is recommended for large quantities and the tube variant for individual strains. Up to 25-30 colonies (plaques) are inoculated into a petri dish and a "dash" inoculation is made into oblique agar in tubes. The cultures are incubated for 24 h at 37 degrees C. After 3-min staining (100 micrograms/ml) of the resultant cultures three phenomena are observed due to the presence of a virulence plasmid with molecular weight of 45-48 megadalton in the strain: violet staining (CV+ test), adhesion to substrate (adhesion+), and adhesion of Yersinia cells to each other (autoadhesion+). Strains with these phenotypical signs are virulent. The proposed method is simple, informative, and reliably detects virulent strains of Yersinia among apathogenic and pathogenic species (variants) isolated from clinical or epidemiologically significant materials.

Bacterial Typing Techniques↗
PubMed1996

Lethal infection by a previously unrecognised metazoan parasite.

BACKGROUND: New microbial pathogens or variant clinical manifestations of known organisms may be first found in immunodeficient patients. An HIV-infected man developed a rapidly-enlarging abdominal mass, suggestive of a neoplasm, that subsequently invaded his liver and caused death. Initial studies showed unusual tissue morphology that could not be matched with any known disease process. METHODS: Tissues obtained from biopsy at laparotomy and necropsy were studied by light microscopy, immunohistochemistry, electron microscopy, and broad-range ribosomal DNA-amplification and sequence analysis. FINDINGS: Tissue lesions were characterised by peculiar cytoplasmic sacs containing minute cells with very prominent nucleoli. The pathological process was recognised as a parasitic infection, although its features were different from those of any known eukaryotic pathogen. Phylogenetic analysis of a 357 bp 18S rDNA sequence amplified directly from the involved tissue indicated that the causative agent was a previously-uncharacterised cestode. INTERPRETATION: Fatal disease produced by this newly recognised cestode may not be limited to immunodeficient hosts. Awareness of this metazoan infection may allow early diagnosis-by morphology and DNA sequence analysis--and perhaps successful treatment of subsequent cases.

AIDS-Related Opportunistic Infections↗
PubMed2002

Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome.

Autosomal recessive Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes which code for the alpha3 and alpha4 chains of type IV collagen. These mutations result in haematuria, progressive renal impairment and often hearing loss, lenticonus and retinopathy. We describe here the mutations demonstrated by screening the 47 coding exons of the COL4A4 gene in six families with autosomal recessive Alport syndrome using PCR-single stranded conformational polymorphism (SSCP) analysis. Six sequence variants were identified. These included three novel mutations (2846delG, 2952delG and S969X) in exons 30 - 32 that all resulted in premature stop codons. These mutations were demonstrated in the heterozygous form in 3 families, and the S969X mutation was also present in the homozygous form in one of the two consanguinous families. These three mutations accounted for 40% (4/10) of the total mutant alleles in the six families studied. Six of the seven (86%) individuals with autosomal recessive Alport syndrome who had these mutations in the compound heterozygous or homozygous forms developed renal failure in adulthood, as well as hearing loss and ocular abnormalities. Haematuria was present in 15 of the 17 (88%) heterozygous mutation carriers. The other non-pathogenic sequence variants noted in COL4A4 included a nonglycine missense variant (L1004P), an intronic variant (4731-8 T>C) and a neutral polymorphism (V1516V).

Adult↗
PubMed1998

Mucosal transmission of pathogenic CXCR4-utilizing SHIVSF33A variants in rhesus macaques.

Infection of macaques with chimeric simian/human immunodeficiency virus (SHIV) expressing the envelope protein of HIV-1 provides a model system for studying HIV-1 infection in humans. To this end, four rhesus macaques (Macaca mulatta) were given a single intravaginal (IVAG) inoculation of cell-free SHIVSF33A and longitudinal samples of peripheral blood and lymph nodes were analyzed for viremia, antigenemia, and various T-cell populations. Rhesus macaques infected IVAG with SHIVSF33A demonstrated a dramatic decrease in the CD4(+) PBMC subset in the initial weeks after viral exposure, a time that corresponded to peak in plasma viremia and antigenemia. Within 4 months of SHIVSF33A inoculation, partial to complete rebound of the CD4(+) PBMC was seen in these animals. Notably, the regeneration of the CD4(+) subset was associated with regeneration of the naive T-cell population and was concordant with clearance of plasma viremia. DNA heteroduplex tracking assays revealed transmission of minor variants within the SHIVSF33A inoculum to the IVAG-inoculated animals. The cell-free SHIVSF33A inoculum as well as virus isolated from animals early after transmission used the chemokine molecule CXCR4 as the primary cellular coreceptor, demonstrating that viruses expressing envelope glycoproteins of the syncytia inducing (SI) phenotype can be transported across the vaginal mucosa. Although none of the animals has yet to develop clinical symptoms of simian AIDS (SAIDS), infectious virus and viral nucleic acids could be persistently isolated from each animal. Furthermore, animals transfused with blood from IVAG-infected macaques drawn 2 weeks after inoculation suffered a more profound and sustained CD4(+) T-cell loss, persistent plasma viremia, and the development of SAIDS in one animal, indicating that IVAG-passaged SHIVSF33A was pathogenic. Taken together, these results establish that a pathogenic CXCR4-utilizing SHIVSF33A species crossed the cervicovaginal mucosa. Different courses of infection in the IVAG versus transfusion animals suggest that host-mediated responses elicited upon transmission across mucosal barriers may serve to limit viral replication and delay disease progression in the IVAG-infected animals.

Acquired Immunodeficiency Syndrome↗