Generation of the virion envelope and egress of the enveloped virion

The lipid bilayer of the membrane envelope of the viruses that bear them is derived from the infected cell. Few (if any) viral genes directed toward lipid biosynthesis or membrane assembly are yet identified. While the lipid bilayer is entirely cellular, the envelope is made virus specific by the insertion of one or several virus-encoded membrane proteins that are synthesized during the replication cycle.

Some of the patterns of envelopment at the plasma membrane for viruses that assemble in the cytoplasm are shown in Fig. 6.8. Viral glycoproteins, originally synthesized at the

Fig. 6.8 Insertion of glycoproteins into the cell's membrane structures and formation of the viral envelope. The formation of viral glycoproteins on the rough endoplasmic reticulum parallels that of cellular glycoproteins except that viral mRNA is translated (a). Full glycosylation takes place in the Golgi bodies, and viral glycoproteins are incorporated into transport vesicles for movement to the cell membrane where they are inserted (b). At the same time (c), viral capsids assemble and then associate with virus-modified membranes. This can involve the interaction with virus-encoded matrix proteins that serve as "adapters." Budding takes place (d,e) as a function of the interaction between viral capsid and matrix proteins and the modified cellular envelope containing viral glycoproteins.

Synthesis and co-translational membrane insertion of viral glycoproteins

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Free infectious virus rough endoplasmic reticulum and then processed through the Golgi apparatus, arrive at the site of budding with their carboxy termini in the cytoplasm and their amino termini on the outside of the cell. At both sites enveloped viruses recruit cellular proteins needed to pinch off the cytoplasmic membrane stalk connecting the budding enveloped particle to the cell surface.

Many viruses, including retroviruses, bud from the surface of the infected cell. Recently, the use of atomic force microscopy (outlined in Chapter 9, Part III) has provided dramatic visualization of this process as shown in Fig. 6.9. Virions associate through capsid interactions with modified cytoplasmic membranes leading to the formation of "blebs" on the surface of the plasma membrane. This process then continues until a bud is formed which then extends outward and breaks off forming a complete enveloped virion. The final stage of budding requires the action of one of the three cellular protein complexes primarily involved in cytoplasmic vesicle formation. These protein complexes normally function to pinch off budding vesicles from the parental membrane and carry out the same role in the final budding of the virion.

For viruses budding at other subcellular locations (such as the bunyaviruses, which bud into the Golgi itself; or herpesviruses, which bud from the nuclear membrane and then into exocy-totic vesicles), a similar process occurs. In each case, the viral glycoproteins contain trafficking signals that direct the protein to its destination, using host cell machinery for this purpose. The plasma membrane of many cells in organized tissue is asymmetrical, and some viruses have evolved to utilize this asymmetry. Thus, certain viruses (e.g., influenza viruses) bud from the apical surface of such cells while others (e.g., vesicular stomatitis virus) bud from the basolat-eral surface. Using elegant recombinant DNA techniques to produce hybrid versions of the relevant proteins, the trafficking signals in these cases were shown to reside in the amino terminal portion of the viral glycoprotein.

Specific details of envelope formation and virion release are complex for nuclear replicating enveloped viruses exemplified by the herpesviruses. As outlined earlier, capsid formation takes place in the nucleus and full capsids presumably associate with tegument (matrix) proteins near the nuclear membrane that has become modified by inclusion of viral glycoproteins glycosylated in the cellular Golgi apparatus. Recently, Mettenleiter and colleagues have provided persuasive evidence using electron microscopy and defined viral mutants that formation of extracellular infectious virus involves two cycles of envelopment. A specific viral glycoprotein is incorporated into the inner nuclear membrane, and viral capsids bud into the lumen between the inner and outer nuclear membranes. This enveloped "pre-virion" then infects the cytoplasm through fusion with the outer nuclear membrane resulting in the loss of this pre-envelope. Subsequently, the capsids acquire their mature envelope by budding into exocytotic vesicles, and enveloped virus is transported to the cell surface for release. The process is very elegantly shown in the electron micrographs of the exocytosis of pseudorabies virus included in Fig. 6.10. This process will be described in more detail in Chapter 17 (Part IV) where herpesvirus replication is described.

Surface glycoproteins

Surface glycoproteins

  1. 6.9 Visualization of the budding of an enveloped virion from the plasma membrane of an infected cell. (a) Viral glycoproteins processed in the endoplasmic reticulum and Golgi apparatus are transferred to the plasma membrane forming a virus-modified region of envelope. Depending on the virus, the C-terminal cytoplasmic portions of the viral glycoproteins may associate with other viral proteins of the matrix. The modified region of the plasma membrane can specifically associate with mature virions assembled inside the infected cell. This association leads to budding and release of mature enveloped virions. (b) The appearance of enveloped Murine Leukemia Virus (a retrovirus) at the surface of an infected cell as visualized by atomic force microscopy is also shown. Here the background plasma membrane of the cell has a slightly different appearance due to differences in the membrane-associated proteins present and the budding of the virus at the surface forming enveloped virions is apparent. (Courtesy of Yuri G Kuznetsov and Alex McPherson, University of California, Irvine.)
  2. 6.9 Visualization of the budding of an enveloped virion from the plasma membrane of an infected cell. (a) Viral glycoproteins processed in the endoplasmic reticulum and Golgi apparatus are transferred to the plasma membrane forming a virus-modified region of envelope. Depending on the virus, the C-terminal cytoplasmic portions of the viral glycoproteins may associate with other viral proteins of the matrix. The modified region of the plasma membrane can specifically associate with mature virions assembled inside the infected cell. This association leads to budding and release of mature enveloped virions. (b) The appearance of enveloped Murine Leukemia Virus (a retrovirus) at the surface of an infected cell as visualized by atomic force microscopy is also shown. Here the background plasma membrane of the cell has a slightly different appearance due to differences in the membrane-associated proteins present and the budding of the virus at the surface forming enveloped virions is apparent. (Courtesy of Yuri G Kuznetsov and Alex McPherson, University of California, Irvine.)

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Fig. 6.10 The envelopment and egress of a herpesvirus. Electron micrographs of exocytosis of pseudorabies virus in the cytoplasm of the infected cell; release of enveloped virions is clearly shown. The bars represent 150 nm. (Micrographs reprinted with the kind permission of the American Society for Microbiology from Granzow H, Weiland F, Jöns A, Klupp B, Karger A, Mettenleiter T. Ultrastructural analysis of the replication cycle of pseudorabies virus in cell culture: a reassessment. Journal of Virology 1997;71:2072-2082.)

Fig. 6.10 The envelopment and egress of a herpesvirus. Electron micrographs of exocytosis of pseudorabies virus in the cytoplasm of the infected cell; release of enveloped virions is clearly shown. The bars represent 150 nm. (Micrographs reprinted with the kind permission of the American Society for Microbiology from Granzow H, Weiland F, Jöns A, Klupp B, Karger A, Mettenleiter T. Ultrastructural analysis of the replication cycle of pseudorabies virus in cell culture: a reassessment. Journal of Virology 1997;71:2072-2082.)

QUESTIONS FOR CHAPTER 6

1 Briefly describe the two modes that enveloped viruses use for entry into their host cells.

2 How do nonenveloped viruses enter their host cells? Describe in detail one example.

3 How do plant viruses enter their host cells? What feature of the plant cell's architecture dictates these modes of entry?

5 Simple virus capsids are found in two types of structural arrangements: helical and icosahedral. What are the key features in the assembly of these two kinds of particles?

6 How do enveloped viruses acquire their membranes during their maturation in animal cells?

4 Describe how the T-even bacteriophage attaches and enters the host cells. Which part of the virus particle enters the cell?

Host Immune Response to Viral Infection - The Nature of the Vertebrate Immune Response

CHAPTER

  • THE INNATE IMMUNE RESPONSE - EARLY DEFENSE AGAINST PATHOGENS
  • Toll-like receptors
  • Defensins
  • THE ADAPTIVE IMMUNE RESPONSE AND THE LYMPHATIC SYSTEM
  • Two pathways of helper T response - the fork in the road
  • The immunological structure of a protein
  • Role of the antigen-presenting cell in initiation of the immune response

Clonal selection of immune reactive lymphocytes Immune memory Complement-mediated cell lysis

  • CONTROL AND DYSFUNCTION OF IMMUNITY
  • Specific viral responses to host immunity Passive evasion of immunity - antigenic drift

Passive evasion of immunity - internal sanctuaries for infectious virus

Passive evasion of immunity - immune tolerance

Active evasion of immunity - immunosuppression

Active evasion of immunity - blockage of MHC antigen presentation

  • Consequences of immune suppression to virus infections
  • MEASUREMENT OF THE IMMUNE REACTION
  • Measurement of cell-mediated (T-cell) immunity
  • Measurement of antiviral antibody Enzyme-linked immunosorbent assays (ELISAs) Neutralization tests

Inhibition of hemagglutination Complement fixation

# QUESTIONS FOR CHAPTER 7

The immune system that protects the body from invading pathogens is composed of two different parts: the innate immune response and the adaptive immune response. The innate immune response is a generalized response that "senses" certain proteins or molecules that are found on, or produced by, bacteria, viruses, or fungi. This response is the earliest antipathogen defense and results in a rather nonspecific inflammatory response. In addition, the innate response helps to signal the body to the presence of an invading pathogen, and helps promote the more specific and potent adaptive immune response, which involves B- and T-cell responses and must be activated.

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