|Institution||School of Medicine and Dentistry|
|Address||University of Rochester Medical Center|
School of Medicine and Dentistry
601 Elmwood Ave, Box 777
Rochester NY 14642
1) Entry of enveloped viruses
Viral entry includes viral binding to receptors, membrane fusion, uncoating and trafficking. My work on viral entry began by initiating the use of Sendai virus (murine parainfluenza virus type 1) with liposomes that contained a viral receptor in the membrane. This model system shows what steps in viral entry are primarily determined by virus components and gives a very simple system to search for new principles. The following new principles were found. 1) Sialic acids were long known to have receptor activity for parainfluenza and influenza viruses, but it was assumed viral receptors were sialoglycoproteins. With liposomes it was shown that gangliosides (sialoglycolipids) can also serve as receptors. 2) Binding occurs at temperatures as low as 0-4°C. Adding virus to liposomes containing gangliosides at 4°C and raising the temperature to 37°C causes the liposomes to envelope the bound viruses. Others followed this up by showing that circumferential binding also causes the initial step of phagocytosis by macrophages. 3) Sendai virus membranes fuse with ganglioside-containing liposomes. This shows that the virus directs fusion and only requires the host to present virus receptor. Further work showed that Sendai virus fuses at the leading edge of the area of the envelopment caused by receptor binding. The high curvature of the leading edge in the liposome membrane changes the membrane bilayer in ways that facilitate membrane fusion. 4) Influenza virus also fuses with liposomes containing gangliosides at neutral pH; whereas, it has been argued that influenza virus requires low pH to fuse its membrane. 5) "Uncoating" involves changes in a viral particle and release of the viral contents into the cell. Electron micrographs suggested that uncoating is an active process, whereas, previously it has been thought a passive result of fusion. A review of recent literature suggested that, when a virus particle is intact, uncoating is different from the generally used model derived in 1968 from experiments using damaged particles.
2) Persistent viral infections
Many viruses from different viral families can form a persistent infection. Viral persistence is more likely to occur if the infection is in the very young and especially in fetuses. Rubella virus is an example of a virus that forms a persistent infection. Rubella-infected fetuses continue to shed virus at birth and for months thereafter. The autopsies of fetuses with congenital rubella syndrome revealed that many tissues were infected. When cells derived from infected tissues were made into cell cultures, the cells were persistently infected. Some infants with congenital rubella syndrome have problems that show up after infancy. These include endocrine problems, late onset of loss of hearing, late onset of ocular problems and neurological problems, which include autism. Consideration of late occurring problems associated with a virus raises the question whether the persistent virus is present in low amounts and causing alterations in the affected organ or whether the virus could have altered the immune system, which then causes the pathology. Some women who accidentally received rubella vaccine during pregnancy had infants who shed vaccine virus at and beyond birth. Thus rubella vaccine virus retained the ability to form a persistent infection, although the multiple viral mutations involved in attenuation changes the infection. For some persistent virus infections a mother who was infected previously can infect her infant in utero. For some other persistent viruses, like rubella, it has not been shown whether the virus can persist long enough so that it could cause infection of the placenta and fetus if the mother became pregnant considerably after the infection. Such an infection might perhaps first express itself clinically as one of the later complications.
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