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Baltimore classification
Overview
Baltimore classification groups viruses together based on their manner of mRNA synthesis.
Characteristics directly related to this include whether the genome is made of deoxyribonucleic
acid (DNA) or ribonucleic acid (RNA), the strandedness of the genome, which can be either
single- or double-stranded, and the sense of a single- stranded genome, which is either positive
or negative. The primary advantage of Baltimore classification is that by classifying viruses
according to the aforementioned characteristics, viruses that behave in the same manner can
be studied as distinct groups. There are seven Baltimore groups numbered with Roman
numerals, listed
hereafter.[1]
Baltimore classification was created in 1971 by virologist David Baltimore. Since then, it has
become common among virologists to use Baltimore classification alongside standard virus
taxonomy, which is based on evolutionary history. In 2018 and 2019, Baltimore classification
was partially integrated into virus taxonomy based on evidence that certain groups were
descended from common ancestors. Various realms, kingdoms, and phyla now correspond to
specific Baltimore groups.
Group I: double-stranded DNA viruses
Group II: single-stranded DNA viruses
Group III: double-stranded RNA viruses
Group IV: positive sense single-stranded RNA
viruses Group V: negative sense single-stranded
RNA viruses
Group VI: single-stranded RNA viruses with a DNA intermediate in their
life cycle Group VII: double-stranded DNA viruses with an RNA
intermediate in their life cycle
Baltimore classification is chiefly based on the transcription of the viral genome, and viruses
within each group typically share the manners by which the mRNA synthesis occurs. While not
the direct focus of Baltimore classification, groups are organized in such a manner that viruses
in each group also typically have the same mechanisms of replicating the viral genome.[2][3]
Because of this, Baltimore classification provides insights into both the transcription and
replication parts of the viral life cycle. Structural characteristics of a virus particle,
called a virion, such as the shape of the viral capsid and the presence of a viral envelope, a lipid
membrane that surrounds the capsid, have no direct relation to Baltimore groups, nor do the
groups necessarily show genetic relation based on evolutionary history.[1]
Visualization of the seven groups of virus according to the Baltimore Classification
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Classification
DNA viruses
DNA viruses have genomes made of deoxyribonucleic acid (DNA) and are organized into two
groups: double- stranded DNA (dsDNA) viruses, and single-stranded DNA (ssDNA) viruses. They
are assigned to four separate realms: Adnaviria, Duplodnaviria, Monodnaviria, and Varidnaviria.
Many have yet to be assigned to a realm.
Group I: double-stranded DNA viruses
The first Baltimore group contains viruses that have a double-stranded DNA (dsDNA) genome. All
dsDNA viruses have their mRNA synthesized in a three-step process.
First, a transcription preinitiation complex (Google search) binds to the DNA upstream of
the site where transcription begins, allowing for the recruitment of a host RNA
polymerase.
Second, once the RNA polymerase is recruited, it uses the negative strand as a template
for synthesizing mRNA strands.
Third, the RNA polymerase terminates transcription upon reaching a specific signal, such
as a polyadenylation site(Google search).[4][5][6]
dsDNA viruses make use of several mechanisms to replicate their genome.
Bidirectional replication, in which two replication forks are established at a replication
origin site and move in opposite directions of each other, is widely used.[7]
A rolling circle mechanism that produces linear strands while progressing in a loop
around the circular genome is also common.[8]
Some dsDNA viruses use a strand displacement method whereby one strand is
synthesized from a template strand, and a complementary strand is then synthesized
from the prior synthesized strand, forming a dsDNA genome.[9]
Lastly, some dsDNA viruses are replicated as part of a process called replicative
transposition whereby a viral genome in a host cell's DNA is replicated to another part of
a host genome.[10]
dsDNA viruses can be subdivided between those that replicate
in the nucleus, and as such are relatively dependent on host cell machinery for
transcription and replication, and those that replicate
in the cytoplasm, in which case they have evolved or acquired their own means of
executing transcription and replication (various enzyme for the process). [3]
dsDNA viruses are also commonly divided between
tailed dsDNA viruses, referring to members of the realm Duplodnaviria, usually the tailed
bacteriophages of the order Caudovirales,
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and tailless or non-tailed dsDNA viruses of the realm Varidnaviria.[11][12]
Group II: single-stranded DNA viruses
The second Baltimore group contains viruses that have a single-stranded DNA (ssDNA) genome.
ssDNA viruses have the same manner of transcription as dsDNA viruses. Because the genome is
single-stranded, however, it is first made into a double-stranded form by a DNA polymerase
upon entering a host cell. mRNA is then synthesized from the double-stranded form. The
double-stranded form of ssDNA viruses may be produced either directly after entry into a cell or
as a consequence of replication of the viral genome. [16][17] Eukaryotic ssDNA viruses are
replicated in the nucleus.[3][18]
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Most ssDNA viruses contain circular genomes that are replicated via rolling circle replication
(RCR). ssDNA RCR is initiated by an endonuclease that bonds to and cleaves the positive strand,
allowing a DNA polymerase to use the negative strand as a template for replication. Replication
progresses in a loop around the genome by means of extending the 3′-end of the positive strand,
displacing the prior positive strand, and the endonuclease cleaves the positive strand again to
create a standalone genome that is ligated into a circular loop. The new ssDNA may be packaged
into virions or replicated by a DNA polymerase to form a double-stranded form for transcription
or continuation of the replication cycle.[16][19]
Parvoviruses contain linear ssDNA genomes that are replicated via rolling hairpin replication
(RHR), which is similar to RCR. Parvovirus genomes have hairpin loops at each end of the genome
that repeatedly unfold and refold during replication to change the direction of DNA synthesis to
move back and forth along the genome, producing numerous copies of the genome in a
continuous process. Individual genomes are then excised from this molecule by the viral
endonuclease. For parvoviruses, either the positive or negative sense strand may be packaged
into capsids, varying from virus to virus.[19][20]
Nearly all ssDNA viruses have positive sense genomes, but a few exceptions and peculiarities
exist. The family Anelloviridae is the only ssDNA family whose members have negative sense
genomes, which are circular.[18] Parvoviruses, as previously mentioned, may package either the
positive or negative sense strand into virions.[17] Lastly, bidnaviruses package both the positive
and negative linear strands.[18][21] In any case, the sense of ssDNA viruses, unlike for ssRNA
viruses, is not sufficient to separate ssDNA viruses into two groups since all ssDNA viral
genomes are converted to dsDNA forms prior to transcription and replication.[2]]
RNA viruses
RNA viruses have genomes made of ribonucleic acid (RNA) and comprise three groups: double-
stranded RNA (dsRNA) viruses, positive sense single-stranded RNA (+ssRNA) viruses, and
negative sense single-stranded RNA (-ssRNA) viruses. The majority of RNA viruses are classified
in the kingdom Orthornavirae in the realm Riboviria. The exceptions are generally viroids and
other subviral agents. Some of the latter category, such as the hepatitis D virus, are classified in
the realm Ribozyviria.
Group III: double-stranded RNA viruses
The third Baltimore group contains viruses that have a double-stranded RNA (dsRNA) genome.
After entering a host cell, the dsRNA genome is transcribed to mRNA from the negative strand
by the viral RNA-dependent RNA polymerase (RdRp). The mRNA may be used for translation or
replication. Single-stranded mRNA is replicated to form the dsRNA genome. The 5′-end of the
genome may be naked, capped, or covalently bound to a
viral protein.[22][23]
dsRNA is not a molecule made by cells, so cellular life has evolved antiviral systems to detect and
inactivate viral dsRNA. To counteract this, many dsRNA genomes are constructed inside of
capsids, thereby avoiding detection
inside of the host cell's cytoplasm. mRNA is forced out from the capsid in order to be translated or
to be translocated from a mature capsid to a progeny capsid.[22][23][24] While dsRNA viruses
typically have capsids, viruses in the families Amalgaviridae and Endornaviridae have not been
observed to form virions and as such apparently lack capsids. Endornaviruses are also unusual in
that unlike other RNA viruses, they possess a single, long open reading frame (ORF), or
translatable portion, and a site-specific nick in the 5′ region of the positive strand.[24]
Group IV: positive sense single-stranded RNA viruses
The fourth Baltimore group contains viruses that have a positive sense single- stranded RNA
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(+ssRNA)
20:29 genome. For +ssRNA viruses, the genome functions as mRNA, so no transcription is
required for translation. +ssRNA viruses will also, however, produce positive sense copies of the
genome from negative sense strands of an intermediate dsRNA genome. This acts as both a
transcription and a replication process since the replicated RNA is also mRNA. The 5′-end
may be naked, capped, or covalently bound to a viral
protein, and the 3′-end may be naked or polyadenylated.[26][27][28]
Many +ssRNA viruses are able to have only a portion of their genome transcribed. Typically,
subgenomic RNA (sgRNA) strands are used for translation of structural and movement proteins
needed during intermediate and late stages of infection. sgRNA transcription may occur by
commencing RNA synthesis within the genome rather than from the 5′-end, by stopping RNA
synthesis at specific sequences in the genome, or by, as a part of both prior methods,
synthesizing leader sequences from the viral RNA that are then attached to sgRNA strands.
Because replication is required for sgRNA synthesis, RdRp is always translated first.[27][28][29]
Because the process of replicating the viral genome produces intermediate dsRNA molecules,
+ssRNA viruses can be targeted by the host cell's immune system. To avoid detection, +ssRNA
viruses replicate in membrane- associated vesicles that are used as replication factories. From
there, only viral +ssRNA, which may be mRNA, enters the main cytoplasmic area of the cell.[26]
[27]
+ssRNA viruses can be subdivided between those that have polycistronic mRNA, which encodes
a polyprotein that is cleaved to form multiple mature proteins, and those that produce
subgenomic mRNAs and therefore undergo two or more rounds of translation.[3][30]
Group V: negative sense single-stranded RNA viruses
The fifth Baltimore group contains viruses that have a negative sense, single-stranded RNA (-
ssRNA) genome. mRNA, which is positive sense, is transcribed directly from the negative sense
genome. The first process for - ssRNA transcription involves RdRp binding to a leader sequence
on the 3′ end of the genome, transcribing a 5′ triphosphate-leader RNA that is capped, then
stopping and restarting on a transcription signal which is capped, continuing until a stop signal
is reached.[31] The second manner is similar but instead of synthesizing a cap, RdRp may make
use of cap snatching, whereby a short sequence of host cell mRNA is taken and used as the 5′
cap of the viral mRNA.[32] Genomic -ssRNA is replicated from the positive sense antigenome in a
similar manner as transcription, except in reverse using the antigenome as a template for the
genome. RdRp moves from the 3′-end to the 5′-end of the antigenome and ignores all
transcription signals when synthesizing genomic -ssRNA.[23][33]
Various -ssRNA viruses use special mechanisms for transcription. The manner of producing the
polyA tail may be via polymerase stuttering, during which RdRp transcribes an adenine from
uracil and then moves back in the RNA sequence with the mRNA to transcribe it again,
continuing this process numerous times until hundreds of adenines have been added to the 3′-
end of the mRNA.[34] Additionally, some -ssRNA viruses are ambisense, as both the positive and
negative strands separately encode viral proteins, and these viruses produce two separate
mRNA strands: one directly from the genome and one from a complementary strand.[35][36]
-ssRNA viruses can be subdivided informally between those that have nonsegmented and
segmented genomes. Nonsegmented -ssRNA viruses replicate in the cytoplasm, and segmented
-ssRNA viruses replicate in the nucleus. During transcription, the RdRp produces one
monocistronic mRNA strand from each segment of the genome.[3][23][37]
Reverse transcribing viruses
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Reverse
20:29 transcribing (RT) viruses have genomes made of either DNA or RNA and replicate via
reverse transcription. Two groups of reverse transcribing viruses exist: single-stranded RNA-RT
(ssRNA-RT) viruses, and double-stranded DNA-RT (dsDNA-RT) viruses. Reverse transcribing
viruses are classified in the kingdom Pararnavirae in the realm Riboviria.
Group VI: single-stranded RNA viruses with a DNA intermediate
The sixth Baltimore group contains viruses that have a (positive-sense) single-stranded RNA
genome that has a DNA intermediate ((+)ssRNA-RT) in its replication cycle. [note 1] ssRNA-RT
viruses are transcribed in the same manner as DNA viruses, but their linear genomes are first
converted to a dsDNA form through a process called reverse transcription. The viral reverse
transcriptase enzyme synthesizes a DNA strand from the ssRNA strand, and the RNA strand is
degraded and replaced with a DNA strand to create a dsDNA genome. The genome is then
integrated into the DNA of the host cell, where it is now called a provirus. The host cell's RNA
polymerase II then transcribes RNA in the nucleus from the proviral DNA. Some of this RNA
may become mRNA whereas other strands will become copies of the viral genome for
replication.[37][39][40][41]
Group VII: double-stranded DNA viruses with an RNA intermediate
The seventh Baltimore group contains viruses that have a double-stranded DNA genome that
has an RNA
intermediate (dsDNA-RT) in its replication cycle. dsDNA-RT viruses have a gap in
one strand, which is repaired to create a complete dsDNA genome prior to transcription.[3][37]
dsDNA-RT viruses are transcribed in the same manner as dsDNA viruses,[2] but make use of
reverse transcription to replicate their circular genome while it is still in the capsid. The host
cell's RNA polymerase II transcribes RNA strands from the genome in the cytoplasm, and the
genome is replicated from these RNA strands. The dsDNA genome is produced from
pregenomic RNA strands via the same general mechanism as ssRNA-RT viruses, but with
replication occurring in a loop around the circular genome. After replication, the dsDNA
genome may be packed or sent to the nucleus for further rounds of transcription.[39][43]
Multi-group characteristics
A number of characteristics of viruses are not directly associated with Baltimore classification
but nonetheless closely correspond to multiple, specific Baltimore groups. This includes
alternative splicing during transcription, whether the viral genome is segmented, the host range
of viruses, whether the genome is linear or circular, and different methods of translating viral
mRNA.
Alternative splicing
Alternative splicing is a mechanism by which different proteins can be produced from a single
gene by means of using alternative splicing sites to produce different mRNAs. It is found in
various DNA, -ssRNA, and reverse transcribing viruses. Viruses may make use of alternative
splicing solely to produce multiple proteins from a single pre-mRNA strand or for other specific
purposes. For certain viruses, including the families Orthomyxoviridae and Papillomaviridae,
alternative splicing acts as a way to regulate early and late gene expression during different
stages of infection. Herpesviruses use it as a potential anti-host defense mechanism to prevent
synthesis of specific antiviral proteins. Furthermore, in addition to alternative splicing, because
cellular unspliced RNA cannot be transported out of the nucleus, hepadnaviruses and
retroviruses contain their own proteins for exporting their unspliced genomic RNA out of the
nucleus.[44][45]
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Genome
20:29 segmentation
Viral genomes can exist in a single, or monopartite, segment, or they may be split into more
than one molecule, called multipartite. For monopartite viruses, all genes are on the single
segment of the genome. Multipartite viruses typically package their genomes into a single virion
so that the whole genome is in one virus particle, and the separate segments contain different
genes. Monopartite viruses are found in all Baltimore groups, whereas multipartite viruses are
usually RNA viruses. This is because most multipartite viruses infect plants or fungi, which are
eukaryotes, and most eukaryotic viruses are RNA viruses.[46][47][48] The family Pleolipoviridae
varies
as some viruses are monopartite ssDNA while others are bipartite with one segment being
ssDNA and the other dsDNA.[6][49] Viruses in the ssDNA plant virus family Geminiviridae
likewise vary between being monopartite and bipartite.[47][50]
Host range
Different Baltimore groups tend to be found within different branches of cellular life. In
prokaryotes, the large majority of viruses are dsDNA viruses, and a significant minority are
ssDNA viruses. Prokaryotic RNA viruses, in contrast, are relatively rare. Most eukaryotic
viruses, including most animal and plant viruses, are RNA viruses, although eukaryotic DNA
viruses are also common. By group, the vast majority of dsDNA viruses infect prokaryotes,
ssDNA viruses are found in all three domains of life, dsRNA and +ssRNA viruses are
primarily
found in eukaryotes but also in bacteria, and -ssRNA and reverse transcribing viruses are
only found in eukaryotes.[47][46][51]
Linear vs circular genomes
Viral genomes may be either linear with ends or circular in a loop. Whether a virus has a linear
or circular genome varies from group to group. A significant percentage of dsDNA viruses are
both, ssDNA viruses are primarily circular, RNA viruses and ssRNA-RT viruses are typically
linear, and dsDNA-RT viruses are typically circular.[52][53] In the dsDNA family
Sphaerolipoviridae, and in the family Pleolipoviridae, viruses contain both linear and circular
genomes, varying from genus to genus.[6][49][54]
RNA editing
RNA editing is used by various ssRNA viruses to produce different proteins from a single gene.
This can be done via polymerase slippage during transcription or by post-transcriptional editing.
In polymerase slippage, the RNA polymerase slips one nucleotide back during transcription,
inserting a nucleotide not included in the template strand. Editing of a genomic template would
impair gene expression, so RNA editing is only done during and after transcription. For ebola
viruses, RNA editing improves the ability to adapt to their hosts.[45][55]
Alternative splicing differs from RNA editing in that alternative splicing does not change the
mRNA sequence like RNA editing but instead changes the coding capacity of an mRNA
sequence as a result of alternative splicing sites. The two mechanisms otherwise have the same
result: multiple proteins are expressed from a single gene.[45]
Translation
Translation is the process by which proteins are synthesized from
mRNA by ribosomes. Baltimore groups do not directly pertain to
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the translation
20:29 of viral proteins, but various atypical types of
translation used by viruses are usually found within specific
Baltimore groups:[2][56]
Non-canonical translation initiation:
Viral initiation of translation: used primarily by +ssRNA and ssRNA-RT viruses, various viruses
have evolved mechanisms to initiate translation, such as having internal ribosomal entry
sites to allow for cap-independent translation, having downstream hairpin loops that allow
for cap-dependent translation in the absence of an eIF2 initiation factor, and initiation at a
CUG or other start codon with a leucine amino acid.[57][58]
Leaky scanning: used by various viruses in all Baltimore groups, the 40S ribosomal subunit
may scan through a start codon, thereby skipping an ORF, only initiating translation with the
60S subunit at a subsequent start codon.[59][60]
Ribosomal shunting: used by various dsDNA, +ssRNA, -ssRNA, ssRNA-RT, a dsDNA-RT
viruses, ribosomes will start scanning from a 5′-cap structure then bypass a leader structure in
the mRNA, initiation translation downstream from the leader sequence.[61][62]
Termination-reinitiation: used by some dsRNA and +ssRNA viruses, ribosomes may translate
an ORF, but following termination of translation of that ORF, a proportion of 40S subunits
of the ribosome remain attached to the mRNA as a way to reinitiate translation of a
subsequent ORF.[63]
Non-canonical elongation and termination of translation:
Ribosomal frameshifting: used by various dsDNA, dsRNA, +ssRNA, and ssRNA-RT viruses,
produces merged proteins from overlapping ORFs. This is executed simply by ribosomes
slipping one nucleobase forward or backward during translation.[60][64]
Suppression of termination: also called stop-codon readthrough, used by various dsRNA,
+ssRNA, and ssRNA-RT viruses, certain viruses contain codons in their mRNA that would
normally signal for termination of translation upon being recognized by a release factor
but are instead partially recognized by tRNA during translation, which allows for
continued translation up to the next stop codon in order to produce an extended end of
the viral protein.[65] In viruses, this is often used to express replicase enzymes.[66]
Ribosomal skipping: also called stop-carry on, used by various dsRNA and +ssRNA
viruses, a viral peptide, or amino acid sequence, may prevent a ribosome from
covalently linking a new inserted amino acid, which blocks further translation.
Consequently, the polyprotein is co-translationally cleaved, and a new amino acid
sequence is started, leading to the production of two individual proteins from one ORF.
[62][67]
History
Baltimore classification was proposed in 1971 by virologist David consider establishing
Baltimore in a paper titled Expression of Animal Virus Genomes. It ranks higher than
initially contained the first six groups but was later expanded to include order as well as how
group VII.[37][68][69] Because of the utility of Baltimore classification, it the Baltimore groups
has come to be used alongside standard virus taxonomy, which is based would be
on evolutionary relationships and governed by the International treated among higher
Committee on Taxonomy of Viruses (ICTV).[69] taxa.[69]
From the 1990s to the 2010s, virus taxonomy used a 5-rank system In two votes in 2018
ranging from order to species with Baltimore classification used in and 2019, a 15-rank
system ranging from
conjunction. Outside of the ICTV's official framework, various
realm to species was
supergroups of viruses joining together different families and orders established by the
were created over time based on increasing evidence of deeper ICTV.[69] As part of
evolutionary relations. Consequently, in 2016, the ICTV began to this, the Baltimore
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20:29 for RNA viruses
David Baltimore
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and RT viruses were incorporated into formal taxa. In 2018, the realm Riboviria was established
and initially included the three RNA virus groups. [70] A year later, Riboviria was expanded to
also include both RT groups. Within the realm, RT viruses are included in the kingdom
Pararnavirae and RNA viruses in the kingdom Orthornavirae. Furthermore, the three Baltimore
groups for RNA viruses are used as defining characteristics of the phyla in Orthornavirae.[25]
Unlike RNA viruses and RT viruses, DNA viruses have not been united under a single realm but
are instead dispersed across four realms and various taxa that are not assigned to a realm. The
realms Adnaviria and Duplodnaviria exclusively contains dsDNA viruses,[11][13] Monodnaviria
primarily contains ssDNA viruses but also contains dsDNA viruses,[14] and Varidnaviria
exclusively contains dsDNA viruses, although some proposed members of Varidnaviria, namely
the family Finnlakeviridae, are ssDNA viruses.[12]
Explanatory notes
1. ssRNA-RT viruses are often called retroviruses, although this term is also used to refer
to any reverse transcribing virus as well as specifically to viruses in the ssRNA-RT
family Retroviridae.
References
General bibliography
Cann, A. (2015). Principles of Molecular Virology. Elsevier. pp. 122–127. ISBN 978-0128019559.
Fermin, G. (2018). Viruses: Molecular Biology, Host Interactions and Applications to Biotechnology.
Elsevier. pp. 35–46. doi:10.1016/B978-0-12-811257-1.00002-4 ([Link]
0-12-811257-1.00002
-4). ISBN 978-0128112571. S2CID 89706800
([Link] Lostroh, P. (2019). Molecular and
Cellular Biology of Viruses. Garland Science. ISBN 978-0429664304. Rampersad, S.; Tennant,
P. (2018). Viruses: Molecular Biology, Host Interactions and Applications to
Biotechnology. Elsevier. pp. 55–82. doi:10.1016/B978-0-12-811257-1.00003-6
([Link]
78-0-12-811257-1.00003-6). ISBN 978-0128112571. S2CID 90170103
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