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A virus-virus interaction circumvents the virus receptor requirement for infection by pathogenic retroviruses
David L Wensel1, Weihua Li, James M Cunningham
1Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
During ongoing C-type retrovirus infection, the probability of leukemia caused by insertional gene activation is markedly increased by the emergence of recombinant retroviruses that repeatedly infect host cells. The murine mink cell focus-inducing (MCF) viruses with this property have acquired characteristic changes in the N-terminal domain of their envelope glycoprotein that specify binding to a different receptor than the parental ecotropic virus. In this report, we show that MCF virus infection occurs through binding to this receptor (termed Syg1) and, remarkably, by a second mechanism that does not utilize the Syg1 receptor. By the latter route, the N-terminal domain of the ecotropic virus glycoprotein expressed on the cell surface in a complex with its receptor activates the fusion mechanism of the MCF virus in trans. The rate of MCF virus spread through a population of permissive human cells was increased by establishment of trans activation, indicating that Syg1 receptor-dependent and -independent pathways function in parallel. Also, trans activation shortened the interval between initial infection and onset of cell-cell fusion associated with repeated infection of the same cell. Our findings indicate that pathogenic retrovirus infection may be initiated by virus binding to cell receptors or to the virus envelope glycoprotein of other viruses expressed on the cell surface. Also, they support a broader principle: that cooperative virus-virus interactions, as well as virus-host interactions, shape the composition and properties of the retrovirus quasispecies.
Insights
Recombinant retroviruses spread by binding to receptors or activating other viruses. This dual infection mechanism accelerates leukemia development by enabling faster cell-cell fusion and spread.
Area of Science:
- Virology
- Molecular Biology
- Oncology
Background:
- C-type retrovirus infections increase leukemia risk via insertional gene activation.
- Recombinant retroviruses, like murine mink cell focus-inducing (MCF) viruses, enhance infection through altered envelope glycoproteins and receptor binding.
Purpose of the Study:
- To investigate the infection mechanisms of MCF viruses.
- To elucidate the role of the Syg1 receptor and alternative pathways in MCF virus spread.
- To understand how virus-virus interactions influence retroviral pathogenesis.
Main Methods:
- Analysis of MCF virus infection pathways in permissive human cells.
- Investigation of Syg1 receptor-dependent and -independent infection routes.
- Assessment of trans activation effects on viral spread and cell-cell fusion.
Main Results:
- MCF virus utilizes both Syg1 receptor-dependent and independent pathways for infection.
- Trans activation, via ecotropic virus glycoprotein on cell surfaces, facilitates MCF virus fusion in trans.
- Parallel functioning of these pathways accelerates MCF virus spread and cell-cell fusion.
Conclusions:
- Pathogenic retroviral infection can be initiated by direct receptor binding or by interactions with other viral glycoproteins on cell surfaces.
- Cooperative virus-virus interactions play a significant role in shaping retroviral quasispecies and disease progression.
- Understanding these complex interactions is crucial for developing strategies against retroviral infections and associated leukemias.