Interferons - Viral Multiplication

INTERFERONS

Interferons are host-encoded proteins that provide the first line of defense against viral infections. They belong to the class of molecules called chemokines, which are proteins or glycoproteins that are involved in cell-to-cell communication. Virus infection of all types of cells stimulates the production and secretion of either interferon or interferon , which acts on other cells to induce what is called the antiviral state. Unlike immunity, the interferons are not specific to a particular kind of virus; however, interferons usually act only on cells of the same species. Other agents stimulate the production of interferon γ by lymphoid cells. In this case, interferon appears to play an important role in the im-mune system independent of any role as an antiviral protein .

The signal that leads to the production of interferon by an infected cell appears to be double-stranded RNA. This conclusion is based on the observation that treatment of cells with purified double-stranded RNA or synthetic double-stranded ribopolymers results in the secretion of interferon. Although the mechanisms are largely unclear and probably vary from one virus to another, viral infections in general lead to the accumulation of sig-nificant levels of double-stranded RNA in the cell.

     Changes in the synthesis of a large number of cellular proteins are characteristic of the antiviral state induced by interferon. However, the cells exhibit only minimal changes in their metabolic or growth properties. The machinery to inhibit virus production is mo-bilized only on infection. Interferon has multiple effects on cells, but only three systems have been extensively studied. The first system involves a protein called Mx that is in-duced by interferon and specifically blocks influenza infections by interfering with viral transcription. The second system involves the upregulation of protein kinase that is de-pendent on double-stranded RNA and PKR which phosphorylates and thereby inactivates one of the subunits of an initiation factor (eIF-2) necessary for protein synthesis. In some cases, viruses have evolved quite specific mechanisms to block the action of this protein kinase. The third system involves the induction of an enzyme called 2’,5’ -oligoadenylate synthetase, which synthesizes chains of 2’,5’ -oligo(A) up to 10 residues in length. In turn, the 2’,5’ -oligo(A) activates a constitutive ribonuclease, called RNase L, that de-grades mRNA. The activities of both PKR and 2’,5’ -oligo(A) synthetase require the pres-ence of double-stranded RNA, the intracellular signal that an infection is occurring. This requirement prevents interferon from having an adverse effect on protein synthesis in un-infected cells. In these latter two cases, viral infection of a cell that has been exposed to interferon results in a general inhibition of protein synthesis, leading to cell death and no virus production. A cell that was destined to die anyway from a viral infection is sacri-ficed for the benefit of the entire organism.