Tuhkarokkovirukselle on kehittynyt neuropatogeenisempi variantti

 On havaittu että moni HIV-positiivinen  menehtyi tuhkarokkooon, sen keskushermostoperäiseen taudinkuvaan. Näiltä potilailta on analysoitu tuhkarokkoviruksen fuusioproteiinia (F)   ja hemaglutiniinia (H) . H:n aktivoima F vaikuttaa tavallisesti tuhkarokossa  lipidikalvojen fuusion ja  viruksen soluunpääsyn. Näissä HIV potilaissa oli viruksessa  tapahtunut isäntäkehossa  fuusioproteiinin evoluutiota, mikä teki viruksen paremmin keskushermostoon sopeutuneeksi.  Kyseessä oli eräs pistemutaatio L454W, mikä  vaikutti,  että fuusioproteiini ei ollutkaan  niin riippuvainen H- aktivaatiosta. kuin  tavallisissa  tuhkarokkoviruksissa, vaan  se toimi  itsenäisesti  ja sen lämpöstabiliteetti oli alentunut ja fuusioaktiivisuus noussut. Tutkijat olettavat, että  niillä henkilöillä, joilla tehokas soluimmuuniteetti on kadonnut (kuten HIVpositiivisilla), tuhkarokkovirusvariantti, joka on kuvatullla tavalla muuttanut fuuusiokoneistoaan,  leviää tehokkaammin keskushermostoon (aivoihin).

MBio. 2015 Feb 10;6(1). pii: e02528-14. doi: 10.1128/mBio.02528-14. Measles fusion machinery is dysregulated in neuropathogenic variants.

Jurgens EM¹, Mathieu C, Palermo LM², Hardie D³, Horvat B, Moscona A⁴, Porotto M⁵.

Abstract

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.

IMPORTANCE:

Measles virus has become a concern in the United States and Europe due to recent outbreaks and continues to be a significant global problem. While live immunization is available, there are no effective therapies or prophylactics to combat measles infection in unprotected people. Additionally, vaccination does not adequately protect immunocompromised people, who are vulnerable to the more severe CNS manifestations of disease. We found that strains isolated from patients with measles virus infection of the CNS have fusion properties different from those of strains previously isolated from patients without CNS involvement. Specifically, the viral entry machinery is more active and the virus can spread, even in the absence of H. Our findings are consistent with an intrahost evolution of the fusion machinery that leads to neuropathogenic MV variants.

25.2. 2015