Infectious proteins replication

Which mechanism could induce such a dramatic change of the 3D structure of a protein How could the a —> p conversion of PrP into PrP " account for the pathogenic properties of this protein In 1967 (25 years before Prusiner invented the term prion), a remarkably inspired mathematician, J. S. Griffith, proposed a simple but prophetic model of a disease caused by the replication of an infectious protein. One of his hypothesis was that the brain expressed a "normal" form of the protein, whereas the infectious particle contained an "abnormal" form of the same protein. The abnormal form of the protein was then supposed to bind to the normal brain protein and to convert it into a disease-causing protein. This simple mechanism... 

FIGURE 9.4 Griffith s view of the replication of infectious proteins. The infectious protein is symbolized by a red disk. The brain contains a full reservoir of healthy proteins (green squares) that are converted into infectious entities following contact with the infectious protein. The infectious protein has an abnormal form. Each contact of an infectious protein with a healthy one generates a new infectious protein so that an irreversible chain reaction gradually leads to the transformation of biUions of proteins that acquire an abnormal form and cause disease. 

This long quest was marked by milestones. As already discussed, the obtention of highly purified preparations of infectious scrapie particles was necessary to identify the PrP protein. Circular dichroism studies of PrP and PrP demonstrated the existence of two totally distinct conformations of PrP, one corresponding to the physiologically expressed brain protein and the other to the infectious protein. However, the masterly demonstration of the mechanism of prion replication is that PRNP° mice, which do not express the PrP protein, failed to propagate prion infectivity. Hence, without the brain reservoir of normal PrP proteins, infectious PrP proteins are harmless and unable to cause any disease. If we link this information with the respective structures of PrP and PrP , then we have a molecular mechanism accounting for the replication, by force, of prions invaders in the brain of healthy animals (Fig. 9.5). 

Viruses are small infectious agents composed of a nucleic acid genome (DNA or RNA) encased by structural proteins and in some cases a lipid envelope. They are the causative agents of a number of human infectious diseases, the most important for public health today being acquired immunodeficiency syndrome (AIDS), hepatitis, influenza, measles, and vituses causing diarrhoea (e.g., rotavirus). In addition, certain viruses contribute to the development of cancer. Antiviral drugs inhibit viral replication by specifically targeting viral enzymes or functions and are used to treat specific virus-associated diseases. 

The nonstructural region of the precursor, harboring the viral replication machinery, is cut into its mature components in a maturation reaction in which two viral proteases (NS2-pro and NS3/4A-pro) cooperate. Site-directed mutagenesis of an other wise infectious cDNA has shown that both HCV-encoded proteases are necessary for viral infectivity, but most of the attention has so far been focused on one of them a member of the serine protease family (EC 3.4.21) located in the N-terminal region of the viral NS3 protein. 

The eclipse is the period during which the stages of virus multiplication occur. This is called the latent period, because no infectious virus particles are evident. Finally, maturation begins as the newly synthesized nucleic acid molecules become assembled inside protein coats. During the maturation phase, the titer of active virus particles inside the cell rises dramatically. At the end of maturation, release of mature virus particles occurs, either as a result of cell lysis or because of some budding or excretion process. The number of virus particles released, called the burst size, will vary with the particular virus and the particular host cell, and can range from a few to a few thousand. The timing of this overall virus replication cycle varies from 20-30 minutes in many bacterial viruses to 8-40 hours in most animal viruses. We now consider each of the steps of the virus multiplication cycle in more detail. 

Figure 4.7. a schematic presentation of the role of protease in processing of HIV gag (structural protein) and polymerase pol essential for producing infectious virus. With inactive HIV protease, the virus generated is immature and hence not infectious. The i indicates where HIV protease cleavage occurs in producing the pol gene product essential for viral replication. 

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