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Measles virus entry through the signaling lymphocyte activation molecule governs efficacy of mantle cell lymphoma radiovirotherapy.

ABSTRACT: We developed here a vaccine-identical measles virus (MV) as an oncolytic agent against mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin's lymphoma that is difficult to cure but radiosensitive. We armed the virus with the sodium-iodide symporter, which concentrates iodide within infected cells enabling noninvasive imaging and combination radiovirotherapy. Through high-resolution in vivo and ex vivo imaging, we visualized the spread of infections in primary and metastatic tumors for over 2 weeks after therapy, documenting homogeneous virus seeding and spread restricted to perfused tissue. Infection of metastases was more rapid and intense than primary tumors, achieving isotope uptake within about threefold the efficiency of the thyroid. Virotherapy combined with systemic (131)I resulted in more rapid disease regression than either therapy alone. In addition to ubiquitous CD46, vaccine MV retains cell entry through its immune cell-specific receptor signaling lymphocytic activation molecule (SLAM). We asked whether both receptors could sustain effective oncolysis of MCL. Strikingly, only SLAM-dependent entry sustained efficient viral spread, tumor regression, and prolonged survival. These observations shift the focus of future clinical trials to SLAM-expressing hematologic malignancies and suggest that oncolytic vectors may depend on tissue-specific receptors for both cell entry and activation of responses assisting their replication.

SUBMITTER: Miest TS

PROVIDER: S-EPMC3831037 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Measles virus entry through the signaling lymphocyte activation molecule governs efficacy of mantle cell lymphoma radiovirotherapy.

Miest Tanner S TS Frenzke Marie M Cattaneo Roberto R

Molecular therapy : the journal of the American Society of Gene Therapy 20130805 11

We developed here a vaccine-identical measles virus (MV) as an oncolytic agent against mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin's lymphoma that is difficult to cure but radiosensitive. We armed the virus with the sodium-iodide symporter, which concentrates iodide within infected cells enabling noninvasive imaging and combination radiovirotherapy. Through high-resolution in vivo and ex vivo imaging, we visualized the spread of infections in primary and metastatic tumors for ov ...[more]

PMID: 23913184

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Project description:Upon infection, morbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) initially target immune cells via the signaling lymphocyte activation molecule (SLAM) before spreading to respiratory epithelia through the adherens junction protein nectin-4. However, the roles of these receptors in transmission from infected to naive hosts have not yet been formally tested. To experimentally addressing this question, we established a model of CDV contact transmission between ferrets. We show here that transmission of wild-type CDV sometimes precedes the onset of clinical disease. In contrast, transmission was not observed in most animals infected with SLAM- or nectin-4-blind CDVs, even though all animals infected with the nectin-4-blind virus developed sustained viremia. There was an unexpected case of transmission of a nectin-4-blind virus, possibly due to biting. Another unprecedented event was transient viremia in an infection with a SLAM-blind virus. We identified three compensatory mutations within or near the SLAM-binding surface of the attachment protein. A recombinant CDV expressing the mutated attachment protein regained the ability to infect ferret lymphocytes in vitro, but its replication was not as efficient as that of wild-type CDV. Ferrets infected with this virus developed transient viremia and fever, but there was no transmission to naive contacts. Our study supports the importance of epithelial cell infection and of sequential CDV H protein interactions first with SLAM and then nectin-4 receptors for transmission to naive hosts. It also highlights the in vivo selection pressure on the H protein interactions with SLAM.IMPORTANCE Morbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) are highly contagious. Despite extensive knowledge of how morbilliviruses interact with their receptors, little is known about how those interactions influence viral transmission to naive hosts. In a ferret model of CDV contact transmission, we showed that sequential use of the signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors is essential for transmission. In one animal infected with a SLAM-blind CDV, we documented mild viremia due to the acquisition of three compensatory mutations within or near the SLAM-binding surface. The interaction, however, was not sufficient to cause disease or sustain transmission to naive contacts. This work confirms the sequential roles of SLAM and nectin-4 in morbillivirus transmission and highlights the selective pressure directed toward productive interactions with SLAM.

Dataset Information

Measles virus entry through the signaling lymphocyte activation molecule governs efficacy of mantle cell lymphoma radiovirotherapy.

Publications

Measles virus entry through the signaling lymphocyte activation molecule governs efficacy of mantle cell lymphoma radiovirotherapy.

Similar Datasets

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