Animal virus entry into cells the role of the cellular receptor

Animal viruses must enter the cell in an appropriate manner through a complex plasma membrane composed of a lipid bilayer in which membrane-associated proteins "float" in the upper or lower surface (Fig. 6.1). Some integral membrane proteins form pores (channels) in the membrane for transport of ions and small molecules. Other proteins project from the cell's surface and are modified by the addition of sugar residues (glycosylation). Such glycoproteins serve many functions, including mediating immunity, cellular recognition, cell signaling, and cell adhesion.

Virus infection requires interaction between specific proteins on the surface of the virion and specific proteins on the cell's surface — the receptor for that particular virus. It should be kept in mind that the physiological functions of a cell surface protein utilized as a virus receptor really are for purposes other than viral attachment and entry; some identified viral receptors and their known functions are shown in Table 6.1. The term receptor is just a way of defining the protein by the effect that is being studied — in this case, entry of a virus into a cell.

The type and distribution of receptors utilized by a given virus determines (in large part) both its ability to recognize and enter specific differentiated cells (its tissue tropism) as well as the particular animal species it favors (the virus' host range). For example, CD4 and certain chemokine receptors (usually CCR5 or CXCR4) on some T lymphocytes that are involved in the immune response are recognized by HIV to allow an infection of these lymphocytes. The virus has evolved to recognize CD4 and CCR5 or CXCR4 and subvert their functions. Poliovirus utilizes an interaction with a major intercellular adhesion molecule (ICAM) in its infection. The slow progression of rabies virus up the neural net into the CNS is accomplished

Favored by many viruses as receptors to get physically very near to the cell membrane

Transmembrane glycoprotein (could act as a signal transducer)

Sugar residue

Animal Model Immune Response

Cytoplasmic domain

Inactive protein kinase

Cytoplasmic domain

I Ligand

Monomer

Ligand binding and dimerization

Inactive protein kinase

Active protein kinase

Fig. 6.1 (a) The surface of a "typical" animal cell. The lipid bilayer plasma membrane is penetrated by cell surface proteins of various functions. The proteins that extend from the surface (mainly glycoproteins) can be utilized by different viruses as "tether points" or "anchors" for bringing the virus close enough to the cell surface to initiate the entry process. This interaction between a cell surface protein serving as a virus receptor and the virus itself is highly specific between proteins. Integral membrane proteins, such as those mediating transport of small molecules and ions across the plasma membrane, tend not to project as far into the extracellular matrix and can be utilized by retroviruses, especially, as receptors. Some viral receptors are listed in Table 6.1. (b) The interaction between a cellular surface protein (receptor) and a ligand or co-receptor can lead to chemical and structural changes that transmit signals between the exterior and interior of the cell. This is the process of signal transduction. Here, for example, the binding of ligand with two monomeric receptor proteins leads to dimerization, which, in turn, activates a protein kinase in the cytoplasm. This results in phosphorylation of a target protein, producing further changes in the cell.

by its use of acetylcholine receptors as its port of entry into neurons. These receptors are concentrated at the synapses between neurons, and thus, the virus can "jump" from neuron to neuron without causing destruction of the neuron. This pattern of progression minimizes tissue damage and inflammation resulting in virus "leakage" into the host's circulatory system with ensuing immune response. Finally, sialic acid residues are enzymatically added, as modifications to the glycoproteins of secretory cells, especially of the nasopharynx and respiratory system. Influenza and some other respiratory viruses use these sialic acid residues to specifically target such host cells.

An important factor in the tissue tropism of a given virus is the physical availability of the receptor for interaction with the targeting virus. Poliovirus infects only primates because only primates express the appropriate ICAM utilized as the poliovirus receptor. Further, however, it can attach to and penetrate only specific cells of the small intestine's lining and motor neurons despite the fact that poliovirus-specific ICAMs are present on many other primate cells. In these refractory cells, however, other membrane proteins on the surface apparently mask the receptor. Conversely, if the gene expressing the poliovirus receptor is expressed in a nonprimate cell, such as those of a mouse, using appropriate molecular genetic techniques, the virus can and does initiate a productive infection.

There is another very important factor in entry-mediated tissue tropism in virus infections. Many viruses utilize other proteins on the surface of cells as coreceptors in addition to the major receptor. In the case of HIV, an important coreceptor is one of a group of surface chemokine receptors. There must be a molecular interaction between both the CD4 receptor and the coreceptor for efficient HIV infection. With HIV, the coreceptor also determines tissue tropism. In addition to CD4, macrophages and some T cells express CCR5, which allows HIV variants that recognize this protein to show a marked tropism for these cells. Alternatively, some T lymphocytes express CD4 and a second HIV coreceptor, CXCR4; some strains of HIV show a marked tropism for these cells. Finally, some HIV strains can utilize both coreceptors. Thus, a given virus may utilize a major receptor protein, but require the presence of one or several other proteins in addition. If a certain cell possesses the major receptor but not the coreceptor,

Table 6.1 Some cellular receptors for selected animal viruses.

Name

Cellular function

Virus receptor for

ICAM-1

Intracellular adhesion

Poliovi rus

CD4

T-lymphocyte functional marker

HIV

MHC-I

Antigen presentation

Togavirus, SV40

MHC-II

Antigen presentation/stimulation of

Visnavirus (lentivirus)

B-cell differentiation

Fibronectin

Integrin

Echovirus (picornavirus)

Cationic amino acid

Amino acid transport

Murine leukemia virus

transporter

(oncornavi rus)

LDL receptor

Intracellular signaling receptor

Subgroup A avian leukosis

virus (oncornavirus)

Acetylcholine receptor

Neuronal impulse transducer

Rabies virus

EGF

Growth factor

Vaccinia virus

CR2/CD21

Complement receptor

Epstein-Barr virus

HVEM

Tumor necrosis factor receptor family

Herpes simplex virus

Sialic acid

Ubiquitous component of extracellular

Influenza virus,

glycosylated proteins

reovirus, coronavirus

infection cannot occur or occurs with impaired efficiency so that cell and tissue tropism are altered.

It is also important to understand that some viruses exhibit alternative methods of initiating infection in a cell neighboring the one initially infected via the receptor-mediated route. For example, infection of a cell may lead to membrane changes that allow fusion with a neighboring cell or cells. Then virus can pass freely into the cytoplasm of the uninfected cell without having to pass the plasma membrane; this is a well-established feature of infections with some strains of HSV that cause the formation of large groups of fused cells or syncytia. This and other aspects of virus-induced modifications to the infected cell are discussed in Chapter 10, Part III.

The contact between cells allowing virus spread need not be complete fusion. The close interaction between dendritic cells and other cells of the immune system in induction of the immune response, which is described in Chapter 7, may facilitate the passage of viruses that were taken up but not destroyed. This is clearly an important feature in the pathogenesis of HIV.

The virus itself may possess a surface protein involved in recognition and receptor-mediated entry that is dispensable under certain conditions. An excellent example is the situation with HSV-1 mutants that lack glycoprotein C (gC) on their envelope. As described in somewhat more detail in Part IV (Chapter 17), this glycoprotein interacts with heparan sulfate on the surface of the cell to allow it to come into close proximity with the ultimate receptor. Mutant viruses lacking gC demonstrate significant alterations in the details of their infection and pathogenesis in laboratory animals, but they replicate with excellent efficiency in many cultured cells in the laboratory. Here the culturing and frequent passage of the cells leads to alterations in the cell surface so that gC-negative viruses can "find" their receptors with little difficulty.

Viruses may also inefficiently use other proteins on the surface to infect cells that do not bear the efficient receptor protein. Provided conditions are optimized, these proteins can substitute for the efficient receptor. This substitution is one reason why some viruses can be induced to infect certain cells in culture even though they do not possess the ideal receptor. An example is the ability of SV40 virus to inefficiently infect certain murine and hamster cells in culture. Such infections can be observed with ease in the laboratory, and there is good suggestive evidence that such atypical infections can occur with some frequency under natural conditions. The emergence of new infectious viruses in the environment is often associated with the appearance of a virus infecting a host previously unaffected by it. The emergence of novel infectious viruses is discussed in Chapter 25, Part V.

Some such occurrences can be inferred to result from an inappropriate infection followed by the novel virus adapting to utilize a previously unrecognized receptor. A rare inappropriate infection of an animal virus into a human with subsequent changes in the genetic properties of the virus was suggested to explain the relatively sudden appearance of HIV in the human community. Another example of such an occurrence may explain the sudden appearance of the H5N1 avian influenza virus that is currently spreading worldwide. While the virus has been transmitted from birds to humans in a limited number of cases, it has not yet, at this writing, mutated to allow human to human transmission.

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