Mutations in the H, F, or M Proteins Can Facilitate Resistance of Measles Virus to Neutralizing Human Anti-MV Sera

Kweder, Hasan; Ainouze, Michelle; Cosby, S. L.; Lévy, Camille; Verhoeyen, Els; Cosset, François‐Loïc; Manet, Évelyne; Buckland, Robin

doi:10.1155/2014/205617

Cited by 19 publications

(19 citation statements)

References 32 publications

(51 reference statements)

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“…The HIV-infected patients with MV CNS manifestations identified in the South African epidemic, from whom the variant viruses were isolated, all had low CD4 + T-cell lymphocyte counts, suggesting that those who developed fatal encephalitis had impaired cellular immunity and failed to clear the viral infection in the usual time frame ( 1 , 11 , 12 ). As another explanation for why immune clearance may have failed, it is noteworthy that alterations in MV H, F, or M proteins have been shown to permit MV to escape neutralizing human anti-MV sera in vitro ( 58 ), and some of these mutations were located within several residues of L454W (e.g., L457W). It is feasible that even in the presence of humoral immunity, F L454W may have arisen as an antibody escape variant and replicated without cellular immunity surveillance, despite not being a predominant species in the blood of one of the patients during acute measles; however, the fact that the L454W F-bearing recombinant virus is neutralized by human serum makes this less likely.…”

Section: Discussionmentioning

confidence: 99%

Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

Jurgens

Mathieu

Palermo

et al. 2015

mBio

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Paramyxoviruses, including the human pathogen measles virus (MV), enter host cells by fusing their viral envelope with the target cell membrane. This fusion process is driven by the concerted actions of the two viral envelope glycoproteins, the receptor binding protein (hemagglutinin [H]) and the fusion (F) protein. H attaches to specific proteinaceous receptors on host cells; once the receptor engages, H activates F to directly mediate lipid bilayer fusion during entry. In a recent MV outbreak in South Africa, several HIV-positive people died of MV central nervous system (CNS) infection. We analyzed the virus sequences from these patients and found that specific intrahost evolution of the F protein had occurred and resulted in viruses that are “CNS adapted.” A mutation in F of the CNS-adapted virus (a leucine-to-tryptophan change present at position 454) allows it to promote fusion with less dependence on engagement of H by the two known wild-type (wt) MV cellular receptors. This F protein is activated independently of H or the receptor and has reduced thermal stability and increased fusion activity compared to those of the corresponding wt F. These functional effects are the result of the single L454W mutation in F. We hypothesize that in the absence of effective cellular immunity, such as HIV infection, MV variants bearing altered fusion machinery that enabled efficient spread in the CNS underwent positive selection.

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Section: Discussionmentioning

confidence: 99%

Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

Jurgens

Mathieu

Palermo

et al. 2015

mBio

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“…We speculate that the PEA motif has its effect by a similar mechanism. Previously we showed that mutations in the M protein can affect the conformation of the F and H glycoproteins and thus facilitate resistance to neutralizing anti-MV sera [ 19 ]. Presumably, the PEA motif in the M proteins of wt MV strains induces a particular 3D conformation in the glycoproteins that allows an elevated immune escape and hence an increased potential for persistence.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we showed that vaccine/laboratory strains of MeV are susceptible, like wt MeV strains, to accumulate mutations in their H, F, and M proteins under immune pressure [ 19 ]. However, it would appear that, unlike wt MeV, they lack a phenotypic marker that allows spread and persistence in the CNS.…”

Section: Introductionmentioning

confidence: 99%

“…We therefore decided to compare the primary sequences of SSPE MeV genomes with those from vaccine strains searching for a molecular marker common to all SSPE MeV strains. Initially, we compared primary sequences encoding the H protein but as our previous study [ 19 ] had indicated that mutations in both the F protein and M protein can affect the 3D conformation of the H we extended our search to the primary sequences encoding these latter proteins. Comparing SSPE MeV genomes with that from the Moraten vaccine strain of MeV we observed a triresidue motif PEA (P64, E89, and A209) that is always present in the M proteins from SSPE cases but which is, respectively, SKT (S64, K89, and T209) in the Moraten vaccine M protein.…”

Section: Introductionmentioning

confidence: 99%

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Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis

Kweder

Ainouze

Brunel

et al. 2015

Advances in Virology

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Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV. Why MeV vaccine strains never cause SSPE is completely unknown. Hypothesizing that this phenotypic difference could potentially be represented by a molecular marker, we compared glycoprotein and matrix (M) genes from SSPE cases with those from the Moraten vaccine strain, searching for differential structural motifs. We observed that all known SSPE viruses have residues P64, E89, and A209 (PEA) in their M proteins whereas the equivalent residues for vaccine strains are either S64, K89, and T209 (SKT) as in Moraten or PKT. Through the construction of MeV recombinants, we have obtained evidence that the wt MeV-M protein PEA motif, in particular A209, is linked to increased viral spread. Importantly, for the 10 wt genotypes (of 23) that have had their M proteins sequenced, 9 have the PEA motif, the exception being B3, which has PET. Interestingly, cases of SSPE caused by genotype B3 have yet to be reported. In conclusion, our results strongly suggest that the PEA motif is a molecular marker for wt MeV at risk to cause SSPE.

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“…Defects in the M protein results in the failure to form virus particle facilitating persistence of measles virus in neuronal cells. Failure to form virus particle also helps virus evading neutralizing antibodies …”

Section: Genetic Differences Between Sspe Viruses and Wild Measles Virusmentioning

confidence: 99%

Subacute sclerosing panencephalitis

Garg

Mahadevan

Malhotra

et al. 2019

Reviews in Medical Virology

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Summary Subacute sclerosing panencephalitis (SSPE) is a slowly progressive brain disorder caused by mutant measles virus. SSPE affects younger age groups. SSPE incidence is proportional to that of measles. High‐income countries have seen substantial decline in SSPE incidence following universal vaccination against measles. SSPE virus differs from wild measles virus. Measles virus genome recovered from the autopsied brain tissues demonstrates clustered mutations in virus genome particularly in the M gene. These mutations destroy the structure and functioning of the encoded proteins. Complete infectious virus particle has rarely been recovered from the brain. Human neurons lack required receptor for entry of measles virus inside the neurons. Recent in vitro studies suggest that mutations in F protein confer hyperfusogenic properties to measles virus facilitating transneuronal viral spread. The inflammatory response in the brain leads to extensive tissue damage. Clinically, SSPE is characterized by florid panencephalitis. Clinically, SSPE is characterized by cognitive decline, periodic myoclonus, gait abnormalities, vision loss, and ultimately to a vegetative state. Chorioretinitis is a common ocular abnormality. Electroencephalography (EEG) shows characteristic periodic discharges. Neuroimaging demonstrates periventricular white matter signal abnormalities. In advanced stages, there is marked cerebral atrophy. Definitive diagnosis requires demonstration of elevated measles antibody titers in cerebrospinal fluid (CSF). Many drugs have been used to stabilize the course of the disease but without evidence from randomized clinical trials. Six percent of patients may experience prolonged spontaneous remission. Fusion inhibitor peptide may, in the future, be exploited to treat SSPE. A universal vaccination against measles is the only proven way to tackle this menace currently.

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Mutations in the H, F, or M Proteins Can Facilitate Resistance of Measles Virus to Neutralizing Human Anti-MV Sera

Cited by 19 publications

References 32 publications

Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis

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