Replication

■ The steps in viral replication are as follows:

— Adsorption of the virus to specific receptors on the cell surface.

— Penetration by the virus and intracellular release of nucleic acid.

— Proliferation of the viral components: virus-coded synthesis of capsid and noncapsid proteins, replication of nucleic acid by viral and cellular enzymes.

— Assembly of replicated nucleic acid and new capsid protein.

As shown on p. 376, viruses replicate only in living host cells. The detailed steps involved in their replication are shown below (Fig. 7.4). The reactions of the infected cell (cytopathology, tumor transformation, etc.) are described on p. 392.

Adsorption, penetration, uncoating

Virion -

Protein synthesis Maturation Release v ^ ► Protein ^ ►

mRNA

^Replicase) -Nucleic acid replication -

Capsid

Extraceiiuiar intraceiiuiar

Virions

Extraceiiuiar

Fig. 7.4 See text for details of each step.

Table 7.2 Taxonomy of the Viruses

Nucleic Núcleo- Envelope Virus acid capsid diameter symmetry (nm)

-envelope-

ss/ds 1 (polarity)

ss ds ds ds ss ds

Family Genus

Exemplary important species

Parvoviridae

Papillomaviridae

Polyomaviridae

Adenoviridae

Hepadnaviridae

Herpesviridae

Poxviridae

Erythrovirus

Papillomavirus

Polyomavirus

Mastadenovirus

Ortho-hepadnavirus

Simplexvirus

Varicellovirus

Cytomegalovirus

Roseolovirus

Lymphocrypto-virus

Orthopox Para pox

Parvovirus B19

Human papilloma virus (HPV) BK virus, JC virus Adenoviruses Hepatitis B virus

Herpes simplex virus Varicella zoster virus Cytomegalovirus

Human herpesvirus 6 Epstein-Barr virus

Variola virus, vaccinia virus Orf virus

-envelope-

-helical —envelope-

50-300 100

ss(+)

Picornaviridae

Enterovirus

Poliovirus, echovirus, Coxsackie viruses

Hepatovirus

Hepatitis A virus

Rhinovirus

Rhinovirus 1-117

Parechovirus

Parechoviruses

ss(+)

Astroviridae

Astrovirus

Astroviruses

ss(+)

Caliciviridae

Calicivirus

Hepatitis E virus

ds segm.

Reoviridae

Co I tivirus

Colorado tick fever virus

Orthoreovirus

Reovirus 1-3

Rotavirus

Rotaviruses

ss(+)

Togaviridae

Alphavirus

Sindbis virus

Rubivirus

Rubella virus

ss(+)

Flaviviridae

Flavivirus

Yellow fever virus

Hepacivirus

Hepatitis C virus

ss(+)

Coronaviridae

Coronavirus

SARS virus

ss segm.(-)

Orthomyxoviridae

Influenzavirus

Influenza A, B, C virus

ss(-)

Paramyxoviridae

Pneumovirus

Human respiratory syncytial virus

Paramyxovirus

Human parainfluenza virus 1 and 3

Rubulavirus

Mumps virus

Morbillivirus

Measles virus

ss(-)

Rhabdoviridae

Lyssavirus

Rabies virus

ss(-)

Filoviridae

Filovirus

Marburg virus, Ebola virus

ss segm. (-)

Bunyaviridae

Bunyavirus

Bunyamwera virus

Nairovirus

Crimean-Congo hemorrhagic fever virus

Phlebovirus

Phlebotomus fever virus

Hantavirus

Hantaan virus

ss segm. (+/

- ) Arenaviridae

Arenavirus

LCMV, Lassa virus

ss segm. (+)

Retroviridae

HTLV-retrovirus

HTLV I and II

Spumavirus

Spumavirus

Lentivirus

HIV 1 and 2

Configuration of nucleic acid: ss = single-stranded, ds = double-stranded; 2 = without/with envelope oo

Adsorption. Virus particles can only infect cells possessing surface "receptors" specific to the particular virus species. When a virus encounters such a cell, it adsorbs to it either with the capsid or, in enveloped viruses, by means of envelope proteins. It is therefore the receptors on a cell that determine whether it can be infected by a certain virus.

Receptors

Some aspects of the nature of the receptors are known. These are molecules that play important roles in the life of the cell or intercellular communication, e.g., molecules of the immunoglobulin superfamily (CD4: receptor for HIV; ICAM-1: receptor for rhinoviruses), the complement (C3) receptor that is also the receptor for the Epstein-Barr virus, or glycoproteins the cellular functions of which are not yet known.

Practical consequences arise from this growing knowledge about the receptors: on the one hand, it aids in the development of antiviral therapeutics designed to inhibit the adsorption of the viruses to their target cells. On the other hand, the genetic information that codes for certain receptors can be implanted into cells or experimental animals, rendering them susceptible to viruses to which they would normally be resistant. An example of this application is the use in experimental studies of transgenic mice rendered susceptible to polioviruses instead of primates (e.g., on vaccine testing).

Penetration and uncoating. Viruses adsorbed to the cell surface receptors then penetrate into the cell by means of pinocytosis (a process also known as viropexis). In enveloped viruses, the envelope may also fuse with the cell membrane, releasing the virus into the cytoplasm. Adsorption of such an enveloped virus to two cells at the same time may result in cell fusion. The next step, known as uncoating, involves the release of the nucleic acid from the capsid and is apparently (except in the smallpox virus) activated by cellular enzymes, possibly with a contribution from cell membranes as well. The exact mechanism, which would have to include preservation of the nucleic acid in toto, is not known for all viruses.

Replication of the nucleic acid. Different processes are observed corresponding to the types and configurations of the viral genome (Fig. 7.5).

— DNA viruses: the replication of viral DNA takes place in the cell nucleus (exception: poxviruses). Some viruses (e.g., herpesviruses) possess replicases of their own. The smaller DNA viruses (e.g., polyomaviruses), which do not carry information for their own DNA polymerase, code for poly-peptides that modify the cellular polymerases in such a way that mainly viral DNA sequences are replicated.

Hepadnaviruses: the genome consists of an ssDNA antisense strand and a short sense strand (Fig. 7.5e). The infected cell transcribes an RNA sense strand ("template strand") from the antisense strand. This template strand is integrated in virus capsids together with an RT DNA polymerase. The polymerase synthesizes a complementary antisense DNA and, to "seal off" the ends of the genome, a short sense DNA from the template strand.

— RNA viruses: since eukaryotic cells possess no enzymes for RNA replication, the virus must supply the RNA-dependent RNA polymerase(s) ("replicase"). These enzymes are thus in any case virus-coded proteins, and in some cases are actually components of the virus particle.

Single-stranded RNA: in sense-strand viruses, the RNA functions as mRNA "as is," meaning the information can be read off, and the replicase synthesized immediately. Antisense-strand viruses must first transcribe their genome into a complementary strand that can then act as mRNA. In this case, the poly-merase for the first transcription is contained in the mature virion and delivered into the cell. In ssRNA viruses, whether sense or antisense strands, complementary strands of the genome are produced first (Fig. 7.5a, b), then transcribed into daughter strands. They therefore once again show the same polarity as the viral genome and are used in assembly of the new viral progeny.

Double-stranded RNA: a translatable sense-strand RNA is produced from the genome, which consists of several dsRNA segments (segmented genome). This strand functions, at first, as mRNA and later as a matrix for synthesis of antisense-strand RNA (Fig. 7.5c). Here as well, an RNA-dependent RNA poly-merase is part of the virus particle.

Retroviruses also possess a sense-oriented RNA genome, although its replication differs from that of other RNA viruses. The genome consists of two single-stranded RNA segments with sense polarity and is transcribed by an enzyme in the virion (reverse transcriptase [RT]) into complementary DNA. The DNA is complemented to make dsDNA and integrated in the cell genome. Transcription into sense-strand RNA is the basis for both viral mRNA and the genomic RNA in the viral progeny (Fig. 7.5d).

— Replication of the Viral Genome -

Polymerase Polymerase

L tk

Polymerase Polymerase b

Reverse Integration in Cellular transcriptase cell genome transcriptase

Cell-Virus-Cell ® d RNA DNA DNA DNA RNA

Cellular transcription

Maturation

Cellular transcription

Maturation

e DNA

© DNA partially

RNA DNA

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