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Antibody responses are essential for protection against influenza virus infection. Humans are exposed to a multitude of influenza viruses throughout their lifetime and it is clear that immune history influences the magnitude and quality of the antibody response. The ‘original antigenic sin’ concept refers to the impact of the first influenza virus variant encounter on lifelong immunity. Although this model has been challenged since its discovery, past exposure, and likely one’s first exposure, clearly affects the epitopes targeted in subsequent responses. Understanding how previous exposure to influenza virus shapes antibody responses to vaccination and infection is critical, especially with the prospect of future pandemics and for the effective development of a universal influenza vaccine. [ABSTRACT FROM AUTHOR]

JC virus (JCV) infection of glial cells can lead to progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. A newly described phenotype of the infection is infection of neurons. This distinct clinical and radiological syndrome is named JCV granule cell neuronopathy, characterized by exclusive or predominant cerebellar atrophy. We report the clinical and radiological longitudinal findings of 5 HIV-infected patients referred to us between September 2004 and November 2011 who exhibited JCV granule cell neuronopathy (4 probable cases and 1 possible). The association of immunocompromised status, progressive cerebellar syndrome, MRI abnormalities with cortical cerebellar atrophy and cerebrospinal fluid positive for JCV on PCR allowed for a highly probable diagnosis. The reversal of the immunocompromised status is the only way to stop the disease evolution. Motor functioning can remain impaired, but the illness itself, unlike progressive multifocal leukoencephalopathy, does not seem to threaten life. [ABSTRACT FROM AUTHOR]

Abstract: Lesions affecting the ventral cortex of the left temporal lobe commonly yield a selective reading impairment known as pure alexia. It is thought to result from the disruption or deafferentation of the Visual Word Form Area (VWFA), a region in the left lateral occipitotemporal sulcus activated whenever normal subjects are viewing alphabetic strings. Most pure alexic patients retain the ability to identify single letters, and develop a strategy of letter-by-letter (LBL) reading. We recently studied fMRI activations in LBL readers and clarified the underlying mechanisms. However, LBL reading is a dynamic process which may improve over months or years of practice, although the cerebral bases of this continuing improvement are currently unknown. We had the opportunity to run the same behavioural testing and fMRI experiment a second time in an alexic patient, 8 months after collecting the data reported by Cohen et al. [Cohen, L., Henry, C., Dehaene, S., Molko, N., Lehéricy, S., Martinaud, O., Lemer, C., & Ferrieux, S. (2004). The pathophysiology of letter-by-letter reading. Neuropsychologia, 42, 1768–1780]. We analyze the changes that occurred over this period in the pattern of reading-related activations, while the patient''s LBL reading improved. The activation level decreased in most of the overall network between the two sessions. This general trend contrasted with a focal increase restricted to specific left frontal and parietal areas. When studying the contrast between words and consonant strings, which may be taken as a correlate of LBL reading, we also found a general decrease, except for similar left frontal and parietal regions, which showed a significant increase. We suggest that the pattern of evolution fits with the minimal hypothesis of normal strategic abilities and skill learning, associated with perceptual tuning in right-hemispheric structures able to substitute the disrupted VWFA. [Copyright &y& Elsevier]

Pure alexia is a frequent and incapacitating consequence of left occipitotemporal lesions. It is thought to result from the disruption or the disconnection of the visual word form area (VWFA), a region reproducibly located within the left occipito-temporal sulcus, and encoding the abstract identity of strings of visual letters. Alexic patients often retain effective single letter recognition abilities, and develop an effortful letter-by-letter reading strategy which is the basis of most rehabilitation techniques. We study a patient who developed letter-by-letter reading following the surgical removal of left occipito-temporal regions. Using anatomical and functional MRI in the patient and in normal controls, we show that alexia resulted from the deafferentation of left fusiform cortex, and we analyze the network of brain regions subtending letter-by-letter reading. We propose that during letter-by-letter reading (1) letters are identified in the intact right-hemispheric visual system, with a central role for the region symetrical to the VWFA; (2) letters are serially transferred to the left hemisphere through the intact segment of the corpus callosum; (3) word identity is eventually recovered in the left hemisphere through verbal working memory processes involving inferior frontal and supramarginal cortex. [Copyright &y& Elsevier]

Antibodies targeting the receptor binding site (RBS) of the influenza virus hemagglutinin (HA) protein are usually not broadly reactive because their footprints are typically large and extend to nearby variable HA residues. Here, we identify several human H3N2 HA RBS-targeting monoclonal antibodies (mAbs) that are sensitive to substitutions in conventional antigenic sites and are therefore not broadly reactive. However, we also identify an H3N2 HA RBS-targeting mAb that is exceptionally broadly reactive despite being sensitive to substitutions in residues outside of the RBS. We show that similar antibodies are present at measurable levels in the sera of some individuals but that they are inefficiently elicited by conventional vaccines. Our data indicate that HA RBS-targeting antibodies can be effective against variable viral strains even when they are somewhat sensitive to substitutions in HA residues adjacent to the RBS. • Many mAbs target the RBS of H3 HA, but most are not broadly reactive • Rare H3 HA RBS mAbs are tolerant of substitutions in adjacent sites • Broadly reactive H3 HA RBS Abs are not efficiently elicited by vaccines Zost et al. show that most antibodies targeting the RBS of the H3N2 HAs are not broadly reactive. They identify one broadly reactive H3 HA RBS antibody that is tolerant of substitutions in adjacent antigenic sites but show that these types of antibodies are not efficiently elicited by vaccination. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention of symptomatic COVID-19 disease. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several variants have shown decreased susceptibility to neutralization by vaccine-induced immunity, most notably B.1.351 (Beta), although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of 2 updated mRNA vaccines designed to target SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the spike protein found in B.1.351 and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against B.1.351, while mRNA-1273.211 was effective at providing broad cross-variant neutralization. A third (booster) dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are being evaluated in pre-clinical challenge and clinical studies. [ABSTRACT FROM AUTHOR]

Abstract: A unique case of pyrimethamine-related stroke-like leukoencephalopathy is described. The imputability of the drug is discussed as well as the similarities with the well-known methotrexate neurotoxicity. Owing to the same mode of action of both drugs by inhibition of the enzyme dihydrofolate reductase, this case is highly suggestive of the pathogenetic role of methylation pathway blockade on myelin synthesis resulting in delayed demyelination. This complication could be avoided by a concurrent folinic acid supplementation. [Copyright &y& Elsevier]