Selective Clearance of a Benign Clone of Venezuelan Equine Encephalitis Virus from Hamster Plasma by Hepatic Reticuloendothelial Cells

Abstract

A benign small-plaque clone of Venezuelan equine encephalitis virus was efficiently removed from the blood of inoculated hamsters by adsorption to cells of the hepatic reticuloendothelial system. More than 99% of infectious small-plaque virus, intrinsically labeled with 32P, was cleared from the blood within 30 min of inoculation; 47.6% of the 32P-labeled small-plaque virus inoculum was concentrated in the liver. In contrast, only 0.8% of a virulent large-plaque clone of the virus was cleared from the blood. The affinity of small-plaque virus for liver tissue was confirmed by electron microscopy, since inoculated small-plaque virions were readily visualized in phagocytic vacuoles of hepatic endothelial and Kupffer cells, where they appeared to be undergoing degradation. In contrast, large-plaque virus was not visualized in the liver. A critical determinant of virulence for viruses that do not replicate in hepatic reticuloendothelial cells may be the efficiency with which they are removed from the blood by adsorption to such cells.

Large-Plaque Mutants of Sindbis Virus Show Reduced Binding to Heparan Sulfate, Heightened Viremia, and Slower Clearance from the Circulation

“…Heparin-binding proteins tend to have very short half-lives in the circulation, being rapidly sequestered by tissue HS, particularly in the liver, which has the most highly sulfated HS of any organ (2,35,53,55 reported in several studies that plaque variants of alphaviruses are cleared at variable rates from the circulation after an intravenous injection, with LP variants typically having longer half-lives (19,20,40). Because it is now apparent that one of the factors contributing to increased plaque size is a decreased ability to bind to sulfated polysaccharides, we reexamined the elimination of virus from the circulation.…”

“…The clearance of infectious virus shown here represents actual physical removal of the virus from the circulation and is not due merely to inactivation of infectivity. Previous studies have shown that alphaviruses, regardless of plaque size, are not inactivated by serum or whole blood (22,40), and clearance of radiolabeled alphaviruses from the circulation has been shown to follow kinetics identical to the clearance of PFU (20,21). In order to determine the organ distribution of virus following clearance from the circulation, various radiolabeled viruses were injected intravenously, and selected organs were collected after perfusion of the mice 30 min later.…”

“…3), and the remaining virus was presumed to be distributed widely throughout the body. Another Alphavirus, Venezuelan equine encephalitis virus (VEE virus), shows a similar organ distribution after intravenous injection (20).…”

“…There is reason to suspect that HS-binding viruses may behave in the same manner. A number of studies have shown that alphavirus strains have different clearance rates after intravenous injection, with small-plaque (SP) variants typically having shorter half-lives than large-plaque (LP) variants (20,22,40), but the reason for these findings has been unknown. We have proposed that binding to HS controls both the plaque size and the circulating half-life and that SP variants are cleared more quickly from the circulation because they bind better to HS (4).…”

Pathobiology of the Flaviviruses

“…Studies of nonimmune clearance of alphaviruses by hepatic sinusoidal cells have shown that avirulent strains were cleared from the circulation more rapidly than virulent strains (Jahrling and Sherer, 1973;Jahrling and Gorelkin, 1975;Jahrling, 1976) and that plasma clearance rates in vivo correlated with both increased affinity for cultured cells and pH attachment optima for macrophages near physiological pH (Marker and Jahrling, 1979). Clearance by macrophages of neurotropic flaviviruses is also an important determinant of the course of infection (Zisman et al, 1971;Monath and Borden, 1971;Olson et al, 1975).…”