Chapter 4: Minus-Strand RNA Viruses - Introduction - Overview of the Minus-Strand RNA Viruses

Minus-Strand RNA Viruses

INTRODUCTION

OVERVIEW OF THE MINUS-STRAND

RNA VIRUSES

Seven families of viruses contain minus-strand RNA

[(-)RNA], also called negative-strand RNA, as their

Viruses belonging to four families of (-)RNA viruses, the

genome. These are listed in Table 4.1. Included in the table

Paramyxoviridae, the Rhabdoviridae, the Filoviridae, and

are the names of the genera belonging to these families

the Bornaviridae, contain a nonsegmented RNA genome

and the hosts infected by these viruses. Six of the fami-

having similar organization. They are grouped into the order

lies are known to contain members that cause epidemics

Mononegavirales (mono because the genome is in one piece,

of serious human illness. Diseases caused by these viruses

nega for negative-strand RNA). This was the first order to

include influenza (Orthomyxoviridae), mumps and mea-

be recognized by the International Committee on Taxonomy

sles (Paramyxoviridae), rabies (Rhabdoviridae), encepha-

of Viruses and still is one of only three orders currently rec-

litis (several members of the Bunyaviridae), upper and

ognized. Viruses belonging to the other three families, the

lower respiratory tract disease (numerous viruses in the

Arenaviridae, Bunyaviridae, and Orthomyxoviridae, pos-

Paramyxoviridae), and hemorrhagic fever (many viruses

sess segmented genomes with two, three, and six to eight

belonging to the Bunyaviridae, the Arenaviridae, and the

segments, respectively. Regardless of whether the genome

Filoviridae), as well as other diseases. Bornavirus, the sole

is one RNA molecule or is segmented, the genomes of all

representative of the Bornaviridae, also infects humans

(-)RNA viruses possess a similar suite of genes, as illus-

and may cause neurological illness, but proof of causality

trated in Fig. 4.1. In the Mononegavirales, the order of genes

is lacking. Many of the (-)RNA viruses presently infect

along the genome is conserved among the viruses (although

virtually the entire human population at some point in time

the number of genes may differ). In the viruses with seg-

(e.g., respiratory syncytial virus, influenza virus), whereas

mented genomes, the genes can be ordered in the same way

others did so before the introduction of vaccines against

if the segments are aligned as shown. In addition, many

them (e.g., measles virus and mumps virus). These viruses

features of virion structure and of replication pathways are

are thus responsible for a very large number of cases of

shared among the (-)RNA viruses.

human illness. The diseases caused by such widespread

viruses are usually serious but have a low (although not

Structure of the Virions

insignificant) fatality rate. In contrast, some (-)RNA

viruses, such as rabies and Ebola viruses, cause illnesses

All (-)RNA viruses are enveloped and have helical

with high fatality rates but (fortunately) infect only a small

nucleocapsids. The different families encode either one

fraction of the human population. The (-)RNA viruses

or two glycoproteins (called G in most of the families but

are major causes of human suffering, and all seven fami-

called HA, NA, F, or HN in some, after hemagglutinating,

lies and the viruses that belong to these families will be

neuraminidase, or fusion properties). These glycoproteins

described here.

are present in the viral envelope. In most cases, cleavages

TABLE 4.1 Negative-strand RNA Viruses

Type virusa

Host(s)b

Family/genus

Genome size (in kb)

Transmission

Mononegavirales (nonsegmented)

Rhabdoviridae

1316

Vesiculovirus

VSIV

Vertebrates

Some arthropod-borne

Lyssavirus

Rabies

Vertebrates

Contact with saliva

Ephemerovirus

BEFV

Cattle

Arthropod-borne

Novirhabdovirus

IHNV

Fish

Two genera of plant viruses

Arthropod-borne

Filoviridae

Marburgvirus

Marburg

Vertebrates

Ebolavirus

Zaire Ebola

Vertebrates

Paramyxoviridae

1620

Respirovirus

Sendai

Vertebrates

Airborne

Morbillivirus

Measles

Vertebrates

Airborne

Rubulavirus

Mumps

Vertebrates

Airborne

Henipavirus

Hendra

Vertebrates

Airborne

Avulavirus

Newcastle disease

Birds

Airborne

Pneumovirus

HRSV

Vertebrates

Airborne

Metapneumovirus

TRTV

Turkeys

Airborne

Bornaviridae

Bornavirus

BDV

Vertebrates

Contaminated forage

Segmented Negative Strand RNA Viruses

Orthomyxoviridae

1014.6

Influenzavirus A

Influenza A

Vertebrates

Airborne

8 segments

Influenzavirus B

Influenza B

Vertebrates

Airborne

Influenzavirus C

7 segments

Influenza C

Vertebrates

Airborne

Thogotovirus

6 segments

Thogoto

Vertebrates

Arthropod-borne

Isavirus

8 segments

ISAV

Fish

Waterborne

Bunyaviridae

1120 in 3 segments

Orthobunyavirus

Bunyamwera

Vertebrates

Mosquito-borne

Hantavirus

Hantaan

Vertebrates

Fecesurinesaliva

Nairovirus

Dugbe

Vertebrates

Tickborne

Phlebovirus

Rift Valley fever

Vertebrates

Arthopod-borne

Tospovirus

TSWV

Plants

Thrips

Arenaviridae

1014 in 2 segments

Arenavirus

LCMV

Vertebrates

Urinesaliva

Abbreviations of virus names: VSIV, vesicular stomatitis Indiana virus; BEFV, bovine ephemeral fever virus; IHNV, infectious hematopoietic necrosis

virus; HRSV, human respiratory syncytial virus; TRTV, turkey rhinotracheitis virus; BDV, Borna disease virus; ISAV, infectious salmon anemia virus;

TSWV, tomato spotted wilt virus; LCMV, lymphocytic choriomeningitis virus.

In all cases, "Vertebrates" includes humans.

are required to produce the mature glycoproteins, such as

All (-)RNA viruses have a single major nucleocapsid

cleavage to release a signal peptide, cleavage to separate two

protein (called N) that encapsidates the virion RNA to form

glycoproteins produced as a common precursor, or cleav-

the helical nucleocapsid. Also present in the nucleocapsid

age to activate viral infectivity. The glycoproteins project

is a phosphorylated protein that is required for RNA syn-

from the lipid bilayer as spikes that are visible in the electron

thesis, variously called P (for phosphoprotein) or NS (for

microscope (see, e.g., Fig. 2.18D).

nonstructural protein because it was not originally known to

MONONEGAVIRALES

RHABDOVIRIDAE

VESICULOVIRUS

P/C

(VSIV)

PARAMYXOVIRIDAE

P/V

RUBULAVIRUS

(SV5)

FILOVIRIDAE

p30

FILOVIRUS

sGP

(VP35)

(VP40)

(VP30)

(VP24)

(ZEBOV)

BORNAVIRIDAE

P/X

BORNAVIRUS

(BDV)

SEGMENTED NEGAVIRALES

BUNYAVIRIDAE

S RNA

M RNA

L RNA

BUNYAVIRUS

N NSs

NSm

(SSHV)

S RNA

L RNA

ARENAVIRIDAE

ARENAVIRUS

(LCMV)

ORTHOMYXOVIRIDAE

RNA 3 INFLUENZAVIRUS A

RNA 1

RNA5

RNA8

RNA4

RNA6

RNA 2

(FLUAV)

PB1

PB2

NS1/NS2

M1/M2

Nucleocapsid Genes

Glycoprotein Gene(s)

Polymerase Gene(s)

FIGURE 4.1 Genome organizations of the Negavirales. The genomes of representatives of the four families of

Mononegavirales have been aligned to illustrate functional similarity between gene products. The individual gene segments

of the representatives of the three families with segmented genomes, Bunyaviridae, Arenaviridae, and Orthomyxoviridae,

have been aligned according to similarity of function with those of the Mononegavirales above. Gene expression strategies

for the other genera of Bunyaviridae vary (see Fig. 4.21). Abbreviations of virus names are as follows: VSIV, vesicular

stomatitis Indiana virus; SV5, simian virus 5; ZEBOV, Zaire ebolavirus; BDV, Borna disease virus; SSHV, snowshoe

hare virus; LCMV, lymphocytic choriomeningitis virus; FLUAV, influenza A virus. The gene products are abbreviated as

follows: le is a leader sequence; N is the nucleoprotein; P is the phosphoprotein; M (M1, M2) are matrix proteins; G (G1,

G2) are membrane glycoproteins; F is the fusion glycoprotein; HN is the hemagglutinin-neuraminidase glycoprotein;

L is the RNA polymerase; NA is the neuraminidase glycoprotein; HA is the hemagglutinin glycoprotein; NS (NV, SH,

NSs, NSm) are nonstructural proteins; PB1, PB2, and PA are components of the influenza RNA polymerase; tr is the

trailer sequence. Within a given genome, the genes are drawn approximately to scale. mRNAs for most genes would be

synthesized left to right; however, an arrow over a gene means that it is in the opposite orientation (ambisense genes).

Redrawn from Strauss et al. (1996), Figure 5.

be a component of the virion), as well as a few molecules of

spherical in the electron microscope. The example of influ-

an RNA-dependent RNA polymerase. The polymerase is a

enza virus is shown in Figs. 2.1 and 2.22D, and the paramyxo-

large, multifunctional protein called L in most families but

virus measles virus is shown in Fig. 2.22C. The compositions

is present as three proteins in the Orthomyxoviridae. L and P

of these virions are not rigorously fixed and some variability

form a core polymerase that replicates the viral genome and

in the ratios of the different components, particularly in the

synthesizes mRNAs.

glycoprotein content, is present. The rhabdoviruses are bullet

A matrix protein (M) is present in all of the viruses

shaped or bacilliform and appear more regular (Fig. 2.23), but

except the bunyaviruses and the arenaviruses. M underlies

even here variations in the composition of the glycoproteins in

the lipid bilayer where it interacts with the nucleocapsid. M

the envelope can occur. The filoviruses are filamentous (Fig.

also inhibits host transcription and shuts down viral RNA

2.23). Orthomyxoviruses and paramyxoviruses also produce

synthesis prior to packaging.

filamentous forms as well as round virions (see Fig. 2.25E). In

The (-)RNA virions are heterogeneous to a greater or

fact, clinical isolates of influenza viruses and human respira-

lesser extent. Members of five families often appear roughly

tory syncytial virus are predominantly filamentous.

In contrast to the translation strategy used by the (+)RNA

Synthesis of mRNAs

viruses, the (-)RNA viruses do not produce polypro-

For all (-)RNA viruses, the first event in infection is the

teins that require processing by virally encoded enzymes,

synthesis of mRNAs from the minus-strand genome by the

and virus-encoded proteases are unknown among them.

RNA polymerase present in the nucleocapsid. Because this

However, most of the glycoproteins of the (-)RNA viruses

polymerase is necessary for the production of the mRNAs,

are produced as precursors that are processed by cellular

and because the proteins translated from the mRNAs are

enzymes, and some of these precursors can be considered

required for replication of the genome, the naked genomes

to be polyproteins.

of (-)RNA viruses are not infectious, nor are complemen-

tary RNA copies of the genomes. It has been possible, none-

theless, to rescue virus from cDNA clones of viral genomes

Replication of the Genome

by using special tricks, as described in Chapter 11.

Multiple mRNAs are produced from minus-strand

Replication of the (-)RNA genome requires the pro-

genomes. By definition, each region of the genome from

duction of a complementary copy of the genome, called

which an independent mRNA is synthesized is called a

an antigenome or virus-complementary RNA (vcRNA),

gene. In (-)RNA viruses with segmented genomes, it is

which is distinct from the mRNAs (schematically illus-

obvious that multiple mRNAs are produced (the number

trated in Figs. 1.11C and D). Neither the genomic (-)RNA

of mRNAs produced actually exceeds the number of seg-

nor the antigenomic template produced during replication

ments, as described later). In the Mononegavirales, multiple

is ever free in the cytoplasm. Instead, replication of the

mRNAs arise from the use of a single polymerase entry site

genome, as well as the synthesis of mRNAs, takes place in

at the 3′ end of the genome. The polymerase then recog-

nucleocapsids (sometimes referred to as ribonucleoprotein

nizes conserved start and stop signals at the beginning and

or RNP), which always contain the phosphoprotein and the

end of each gene to generate discrete mRNAs. The amount

polymerase as well as N and the viral RNA. Replication

of mRNA produced for any given gene is controlled by the

can only occur in the presence of ongoing protein synthe-

location of the gene relative to the single polymerase entry

sis to produce the new proteins required to encapsidate the

site, because mRNA synthesis is obligatorily sequential and

genome or antigenome. The mRNAs can be synthesized in

attenuation occurs at each gene junction. Thus, more mRNA

the absence of viral protein synthesis and lack encapsida-

for the proteins encoded 3′ in the genome is made and more

tion signals, so that they are released into the cytoplasm

protein is thus translated from these genes. The N protein,

where they can associate with ribosomes and be translated.

required for encapsidation of both genome and antigenome,

Thus, early after infection, mRNAs are synthesized. After

is thereby produced in the largest quantities and the RNA

translation of the mRNAs, which leads to production of

polymerase, needed in the smallest quantities, is made in the

sufficient amounts of viral proteins, a switch to the produc-

smallest quantities. The synthesis of mRNAs is described in

tion of antigenomes for use as templates occurs, followed

more detail in the sections on Rhabdoviridae.

by production of genomic RNA from the antigenomic

Most of the mRNAs are translated into a single protein,

templates.

but a few of the genes produce mRNAs that are translated

The genomes (or genome segments) of all (-)RNA

into more than one product. Multiple products can be pro-

viruses have sequences at the ends that are complementary

duced from the same gene by the use of alternative trans-

(so-called inverted terminal repeats). In the bunyaviruses,

lation initiation codons during translation of an mRNA; by

the RNAs form panhandles, circular structures that are vis-

the introduction of nontemplated nucleotides during mRNA

ible in the electron microscope. Panhandles have also been

synthesis, which results in a shift in the reading frame; or by

reported for influenza A virus. In other viruses, circles have

splicing of an mRNA. The P genes, in particular, of most

not been seen but may form transiently during replication.

of the (-)RNA viruses are translated into multiple products,

It is possible that these complementary sequences exist to

and two of the segments of influenza virus, which replicates

promote cyclization of the RNA, which may be required

in the nucleus, can be spliced to produce a second mRNA

for replication of the genome or synthesis of mRNAs. It has

encoding a different product. In no case are the mRNAs exact

been shown for influenza A virus that the viral RNA repli-

complements of virion RNAs. This is obvious in the case

case interacts with both ends of the RNA during synthesis of

of the Mononegavirales, where as many as 710 mRNAs

RNA, similar to the story for alphaviruses and flaviviruses

are produced from a single long genomic RNA, but is also

described in Chapter 3. Another possible explanation for the

complementary sequences is that the promoter at the 3′ end

true of the segmented (-)RNA viruses, where the mRNAs

lack cis-active sequences required for encapsidation and

of the genomic RNA that is recognized by the viral RNA

replication that are present near the ends of the antigenome

synthetase for the production of antigenomes is the same, at

least in part, as the promoter at the 3′ end of the antigenomic

segments. Thus, the mRNAs of (-)RNA viruses do not rep-

licate nor are they packaged into virions.

RNA that is used to initiate the production of genomic RNA.

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