Animal Models of Bovine Leukemia Virus and Human T-Lymphotrophic Virus Type-1: Insights in Transmission and Pathogenesis

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Type-1: Insights in
Transmission and
Pathogenesis
Michael D. Lairmore
School of Veterinary Medicine, University of California, Davis, California, 95616;
email: mdlairmore@ucdavis.edu
Annu. Rev. Anim. Biosci. 2014. 2:189–208 Keywords

First published online as a Review in Advance on retrovirus, bovine leukemia virus, transmission, HTLV-1,
December 13, 2013
pathogenesis
The Annual Review of Animal Biosciences is online
at animal.annualreviews.org Abstract
This article’s doi: Bovine leukemia virus (BLV) and human T-lymphotrophic virus type-1
10.1146/annurev-animal-022513-114117
(HTLV-1) are related retroviruses associated with persistent and life-
Copyright © 2014 by Annual Reviews. long infections and a low incidence of lymphomas within their hosts.
All rights reserved
Both viruses can be spread through contact with bodily fluids contain-
ing infected cells, most often from mother to offspring through breast
milk. Each of these complex retroviruses contains typical gag, pol, and
env genes but also unique, nonstructural proteins encoded from the
pX region. These nonstructural genes encode the Tax and Rex
regulatory proteins, as well as novel proteins essential for viral
spread in vivo. Improvements in the molecular tools to test these
viral determinants in cellular and animal models have provided new
insights into the pathogenesis of each virus. Comparisons of BLV and
HTLV-1 provide insights into mechanisms of spread and tumor for-
mation, as well as potential approaches to therapeutic intervention
against the infections.
189
INTRODUCTION
Discovery, Transmission, and Current Epidemiology

Human T-lymphotrophic virus type-1 (HTLV-1) and bovine leukemia virus (BLV) are members of
Deltaretroviridae, a family of retroviruses that includes HTLV-2–4, as well as other nonhuman
viruses, such as simian T-lymphotrophic virus (1, 2). Bovine leukemia (also called enzootic bovine
leukosis) was first described in the late 1800s and was found to be endemic in the twentieth century
in several European countries, notably Denmark and Germany (3). Although suspected for many
years, the viral etiology of enzootic bovine leukemia was not described until 1969, and HTLV-1
was first isolated from the blood of a patient with cutaneous T cell lymphoma in the late 1970s.
The causative role of HTLV-1 in a unique form of T cell lymphoma and leukemia was linked
from epidemiologic studies, and the lymphoma was subsequently classified as adult T cell
leukemia/lymphoma (ATL) (4). In the mid-1980s, HTLV-1 infection was associated with a pro-
gressive myelopathy in Japan and the Caribbean; it was subsequently classified as the same disease
and is referred to as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
HTLV-1 infection has also been associated with a variety of chronic inflammatory diseases,
including infectious dermatitis, uveitis, and arthropathy. From molecular analysis of nonhuman,
primate-derived viral sequences, several related strains have been reported (5). Thus, among
primates, these retroviruses have been characterized as primate T-lymphotrophic viruses, sup-
porting the concept that HTLV-1 infections were originally derived from zoonotic infections of
humans.
Although BLV infection has been reported in multiple ruminant species worldwide, the rates of
BLV infection are most prevalent in dairy cattle (6). Culling of high-producing dairy cattle and
restrictions on exported cattle as a result of BLV infection can lead to significant economic losses.
Country-specific programs have eliminated or reduced BLV infection from many European and
Scandinavian countries. Among infected individuals, both BLV and HTLV-1 are characterized by
low disease incidence after prolonged asymptomatic periods following infection. Like BLV,
HTLV-1 infection is found throughout the world: Approximately 15–20 million carriers exist
worldwide, with endemic areas in Japan, the Caribbean, and Africa (7). After prolonged latency
periods (years), approximately 3–5% of HTLV-1-infected individuals will develop either ATL or
other lymphocyte-mediated disorders.
Both BLV and HTLV-1 are spread through contact with bodily fluids containing infected cells
(8, 9). For both cattle and humans, contaminated blood or cellular blood products are a significant
mode of transmission and a focal point in intervention programs, such as blood screening for
HTLV-1 among donors. Transmission of HTLV-1 is well documented among intravenous drug
users. Importantly for veterinarians and owners, BLV can be spread via routine procedures in-
volving blood from infected animals if proper decontamination practices are not followed. BLV
infection has also been documented from physical transfer of blood from insect bites. The natural
hosts for BLV are domestic cattle and, in some regions, water buffalo. Interestingly, both BLV and
HTLV-1 can be experimentally transmitted to rabbits. BLV has also been experimentally
transmitted to rats, chickens, pigs, goats, and sheep. Sheep develop an abbreviated course of
leukemia and lymphoma from experimental infection and are a model of the disease (10). There is
no evidence that BLV infects humans; extensive epidemiological studies do not indicate any link
between milk consumption and leukemia in people drinking raw milk from infected cattle.
Transfer of infected maternal lymphocytes to offspring is a natural transmission route of both BLV
and HTLV-1. Perinatal contamination of the fetus from infected maternal blood occurs but does
not represent a significant mode of HTLV-1 transmission. The transmission of HTLV-1 through
190 Lairmore
sex is a less efficient route of transmission; however, male-to-female transmission appears to be
more effective. The cell-associated manner of deltaretrovirus transmission is an active area of
research (8). Both viruses are poorly infectious as cell-free virus particles for most cell types. The
exception appears to be dendritic cells, which can be infected by cell-free HTLV-1. Instead, these
viruses use organized cell-to-cell contacts between infected cells and uninfected target cells, which
have been described as virologic synapses, analogous to immunologic synapses during antigen
presentation.
DISEASE ASSOCIATIONS AND COMMON CLINICAL FEATURES

Both BLV and HTLV-1 are associated with adult-onset lymphoma but appear to transform
phenotypically different target cells (Table 1). HTLV-1-associated ATL, in its acute form, is an
aggressive T cell malignancy that typically occurs 20–30 years after infection with HTLV-1 (11).
HTLV-1-associated ATL can express in several clinical presentations but is characterized by

a monoclonal population of T cells that express CD3þ/CD4þ/CD8/CD25þ/HLA-DRþ cell-
surface markers. Approximately 1–5% of HTLV-1-infected patients eventually develop some
form of ATL after a prolonged clinical latency period (Table 1). HTLV-1-infected patients afflicted
with the acute form of ATL (55–75% of all ATL cases) may exhibit fever, malaise, skin lesions,
lymphadenopathy, leukocytosis, and hepatosplenomegaly. The lymphoma is difficult to treat
using standard chemotherapy treatments.
The prolonged and complex interactions between the host and the virus that lead to de-
velopment of HTLV-1-associated ATL are not completely understood, but they have features
in common with BLV-associated lymphoma. HTLV-1-infected, neoplastic monoclonal T cells
originate from polyclonal populations of infected T cells. Similarly, cattle with BLV infections can
develop persistent lymphocytosis, which can be used as a diagnostic marker of the infection.
Within an infected individual, anti-HTLV-1 adaptive immune responses promote emergence of an
oligoclonal population of infected T cells with survival advantages. From this oligoclonal pop-
ulation, a neoplastic T cell clone emerges, typically with a variety of somatic genetic mutations
(12). The HTLV-1 oncoprotein, Tax, initiates immortalization of infected T cells by altering
distinct signaling or genetic events, including cell-cycle control and DNA repair genes. HTLV-1
HBZ, an antisense encoded protein (or its RNA), appears to promote T cell proliferation and
perhaps maintenance of transformation.
HTLV-1-seropositive patients in French Martinique exhibit a neurodegenerative disorder
called tropical spastic paraparesis (TSP) that was subsequently described as a similar clinical
disorder, HTLV-1-associated myelopathy (HAM), in Japanese patients (13). A progressive
chronic myelopathy, HAM/TSP is a result of infiltration of HTLV-1-specific CD4þ and CD8þ
T lymphocytes into the spinal cord, which leads to severe inflammation from production of
proinflammatory cytokines, such as IL-1, IL-6, IFN-g, and TNF-g (14). Interestingly, several other
immune-mediated chronic inflammatory conditions are associated with HTLV-1 infection,
possibly as a result of alteration of the immune system.
Like HTLV-1, most BLV infections in cattle are asymptomatic and are recognized only by
serological testing. Among infected cattle, approximately 30% develop persistent lymphocytosis,
but this is not associated with any clinical signs (15). In those animals that develop disease, clinical
signs are seen in adults typically between four and eight years of age. Cattle with BLV-associated
lymphoma develop multicentric lymphoid tumors in multiple organs, including the intestinal tract
and heart. The primary cells transformed by BLV are B lymphocytes that express IgM, but the virus
also infects monocytes and macrophages (16). Following infection, a virus-driven polyclonal ex-
pansion of lymphocytes promotes viral spread and establishes sufficient integrated proviruses in
www.annualreviews.org Animal Models of BLV and HTLV-1 191

Table 1 Comparison of human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV): transformed cell type,
clinical presentation, and associated diseases
Etiologic Lymphoma/phenotype Neoplastic clinical presentation

agent of transformed cell and outcomes Other associated diseases
HTLV-1 Adult leukemia/lymphoma/ Four clinical types: asymptomatic, Myelopathy/ tropical spastic
CD3þ/CD4þ/CD8/CD25þ/ preleukemic, chronic smoldering, paraparesis (HAM/TSP
HLA-DRþ T cells and acute Dermatitis
Clinical symptoms may include Uveitis, keratoconjunctivitis
malaise, fever, lymphadenopathy, sicca, and interstitial keratitis
hepatosplenomegaly, hypercalcemia, Inflammatory arthropathy
lytic bone lesions, elevated lactate and polymyositis
dehydrogenase, skin infiltrates,
jaundice, weight loss, and

opportunistic infections
Leukocytosis 6 atypical cell
morphology with multilobulated
nuclei flower cells
BLV Adult leukemia/lymphoma/ CD5þ, Multicentric lymphoid tumors in ∼30% of BLV-infected cattle
CD6–, B1 lowþ, B2þ, BoLA lymph nodes, abomasum, heart, develop persistent
class IIþ, and sIgMþ or spleen, kidneys, uterus, spinal lymphocytosis but remain
sIgM– B cells meninges, retrobulbar region, asymptomatic
and brain
infected target cells to maintain the infection. Infected cattle are typically infected for life and
harbor lymphocytes that will divide and maintain the virus through clonal expansion of infected
cells. Viral replication during early dissemination requires viral regulatory proteins for trans-
activation of either viral promoters or promoters that are involved in cell activation or survival (17).
Like HTLV-1, BLV Tax acts to enhance transcription not only of the viral promoter but also of
critical cellular genes that promote proliferation of lymphocytes.
Similar to HTLV-1, BLV-infected cattle form a robust immune response against the viral in-
fection and select for a certain percentage of cell clones that dominate and survive following so-
matic mutation and immune evasion (16). Within this population, those cell clones that develop
a growth advantage continue to proliferate as transformed lymphocytes. In surviving cell clones,
BLV gene expression is maintained at low levels, promoting cell survival (18). Whereas ap-
proximately 30% of cattle with BLV infection may develop persistent lymphocytosis, a subset
(∼1–3%) will develop multicentric lymphosarcoma. A variety of serologic tests are used to di-
agnose the infection and support test and removal programs in several European countries, in-
cluding Denmark and Germany. In other countries, including the United States and Canada,
individual owners may test and remove infected cattle, but national programs are not mandated
currently.
VIRAL GENOME AND TRANSCRIPTIONAL MAP

Both BLV and HTLV-1 are single-stranded diploid RNA viruses that contain genetic information
for structural proteins and enzymes (Gag, Env, reverse transcriptase, protease, integrase) (reviewed
in Reference 1). For both viruses, nucleocapsid (NC), capsid (CA), and matrix (MA) represent the
three proteins produced from the Gag transcript, whereas the env gene encodes for surface unit (SU)
192 Lairmore
and transmembrane unit (TM) proteins. The SU and TM work in a coordinated manner to ac-
complish binding and fusion to cellular membrane receptors during viral entry. Critical enzymatic
proteins of both retroviruses include integrase, reverse transcriptase, and protease.
The genome of HTLV-1 is approximately 9,032 nucleotides long, and in its integrated proviral
form it is flanked by long terminal repeat (LTR) sequences composed of a unique region 30 (U30 ),
a repeated region (R), and a unique region 50 (U50 ) (Figure 1). These LTR elements control viral
gene regulation and replication through synchronized transcriptional initiation and termination,
splicing of viral mRNA, service as sites of polyadenylation of mRNA, and mediation of strand
transfer during reverse transcription. The U3 contains imperfect 21–base pair repeats (Tax re-
sponse elements, or TRE-1) that bind key cellular transcription factors in concert with Tax to
control transcription and act as an active site of chromatin remodeling (reviewed in Reference 19).
In addition to genomic RNA, BLV produces several other forms of RNA: a 5.1-kb species that
encodes for the Env proteins and smaller species of RNA that are translated to produce Tax, Rex,
and the less-abundant R3 and G4 proteins (18). All of these transcripts share a common initiation
site at the boundary of U3 and R (CAP site) and terminate with polyadenylation at the end of R in
the 30 LTR (Figure 2). For both viruses, the U3 region contains canonical promoter CAT sequences
and TATA regions. For BLV, only two of the three TRE sequences in the LTR are required for
infectivity and oncogenicity in the sheep model. For BLV, CRE-binding protein (CREB)- and
activating transcription factor (ATF)-mediated transcription are regulated by well-known kinases,
such as protein kinase A. The BLV 21–base pair enhancer contains internal CRE-like sequences
R U5 gag pro pol env pX U3 R
mRNAs: Proteins:
Unspliced
1 119 4,641
env mRNA Env
AUG
4,641 4,831 6,383
pX-rex-orf I p27Rex
AUG
6,383
pX-orf I p12I
AUG
4,641 4,831 6,478

pX-tax-orf II p30II
AUG
6,875
pX-orf lI p13II
AUG
4,641 4,831 6,950

pX-tax/rex TaxIV
AUG
AUG RexIII
6,950
pX-p21rex p21rex
AUG
5,186 7,270 8,870

HBZ mRNA HBZ
AUG
AUG
Figure 1
Human T-lymphotrophic virus type-1 RNA genome, major RNAs following transcription from provirus and protein gene products.
Diagram of viral RNA and major and minor RNA forms generated from alternative splicing (splice acceptor and donor sites listed
by nucleic acid numerical location in genomic RNA). Proteins encoded from mRNA species are listed on right.

mRNAs: Proteins:
Unspliced
1 305 4,649
env mRNA Env
AUG
1 305 4,649 4,871 7,018

pX-R3 R3
AUG
1 305 4,649 4,871 7,247

pX-tax/rex Rex
AUG
Tax
AUG
502 7,066
pX-G4 G4
AUG
Figure 2
Bovine leukemia virus RNA genome, major RNAs following transcription for provirus and protein gene products. Diagram of viral
RNA and major and minor RNA forms generated from alternative splicing (splice acceptor and donor sites listed by nucleic acid
numerical location in genomic RNA). Proteins encoded from mRNA species are listed on right.
that are similar to the HTLV-1 LTR but different from the consensus CRE sequence. Alteration of
the BLV CRE sequences negatively alters viral replication in sheep (18). Additional U3 elements
provide additional regulatory control for BLV. As in HTLV-1, these include a NFkB-related site,
which for BLV is located between the proximal and middle 21–base pair enhancers and binds in
vitro to several members of the kB family of proteins to promote transcriptional activation (20). In
addition to these U3 elements, BLV expression is regulated by sequences in the R region and an
interferon regulatory factor binding site in the U5 region.
For both BLV and HTLV-1, transcription can be modified through epigenetic alterations, such
as acetylation and methylation. For example, lymphocytes from BLV-infected cattle, when cul-
tured in the presence of histone deacetylase inhibitors, show increased viral expression (21). This
observation has served as a rationale for using histone deacetylase inhibitors to increase virus-
infected cells in HTLV-1 patients to create targets for immune-mediated elimination. Thus, DNA
methylation in theory may serve to regulate LTR-driven transcription and thus represents a
therapeutic target, but minimal modifications of CpG methylation were detected in BLV-infected
cattle and sheep (22). Epigenetic control of BLV and HTLV-1 transcription will likely remain an
active area of investigation.
Both BLV and HTLV-1 contain so-called pX regions, which encode regulatory and non-
structural genes produced by alternative RNA splicing (Figures 1 and 2). For HTLV-1, the 30 end of
the viral genome expresses alternatively spliced mRNAs encoding proteins from open reading
frames (ORFs) I–IV. For HTLV-1, these include ORF I and II encoding p12 (p8), p30, and p13.
HTLV-1 Tax, a transacting transcriptional activator, and Rex, the transporter of unspliced and
single-spliced viral RNA, are encoded from ORF IV and III, respectively. Unique to HTLV-1, the
hbz gene is encoded from a complementary minus-stranded RNA. The BLV pX region contains
ORFs that encode Tax and Rex that perform functions similar to those of HTLV-1. In addition,
BLV pX encodes for two other nonstructural proteins, R3 and G4, which influence in vivo
replication and pathogenesis (23). Although complete details of the role of R3 and G4 in the
pathogenesis of BLV infections are yet to be elucidated, infectious BLV clones that have mutations
in the genes that encode these proteins are limited in their ability to replicate in sheep and lose their
ability to induce lymphomas (24).
194 Lairmore
The LTRs of BLV have parallel regions that serve as sites of cellular transcription factors and
BLV Tax to control transcription of the virus. Like HTLV-1, these TREs bind CREB and a variety
of other related cellular transcription factors, such as ATF-1 and ATF-2 (25). These same regions
also have E-box sequences that bind basic helix-loop-helix proteins, such as c-Myc. The U3 region
of the BLV LTR also serves as a glucocorticoid-responsive element and PU.1/Spi-B binding site
(26). The transcription of the BLV genomic RNA begins at the U3/R boundary of the 50 LTR and
terminates at the polyadenylation site. Like HTLV-1, the BLV genomic RNA is packaged as
a dimer and depends upon RNA folding for efficient packaging. RNA packaging for BLV depends
on basic residues of MA and zinc finger domains of NC (27). Interestingly, exchange of BLV RNA
containing the encapsidation signals with homologous regions of HTLV-1 produces replication-
competent viruses in vitro.
Like in HTLV-1, the 30 end of the genomic BLV RNA contains a highly structured region
(RxRE) needed to mediate RNA transport from the nucleus to the cytoplasm (28). For both
viruses, following transcription and nuclear export, genomic RNA can be directly translated to
yield the gag-pol precursor or incorporated into budding virus particles. BLV viral expression, like
the human retrovirus, is regulated at the posttranscriptional level when BLV Rex binds to the
RxRE. Like HTLV-1, BLV Rex binding is required for nuclear-to-cytoplasmic export of unspliced
and singly spliced transcripts, thus favoring the production of structural proteins for virus
assembly.
In general, the deltaretroviruses have less genetic variation among strains compared with other
retroviruses. Genomic sequence comparisons of BLV isolates from Europe, Japan, and Australia
share approximately 97% of their nucleotide sequences (29). This conservation extends to BLV
env genes characterized from infected cattle from unique geographic regions. Point mutations do
allow for restriction enzyme comparisons but do not predict disease potential or serological status
among infected cattle. The tax gene is also highly conserved for both BLV and HTLV-1, indicating
the importance of the encoded Tax protein for virus replication and spread. Recent studies of env
gene sequence comparisons reveal at least six and perhaps seven BLV clades worldwide, limited to
particular geographic regions (30). Phylogenetic comparisons of different BLV strains, using the
pol gene as a reference, indicate that BLV and primate T-lymphotrophic virus sequences differ by
approximately 40% (30). Among BLV, the sequence divergence was less than 6% in pol and env,
indicating a high degree of conservation among isolates obtained from various regions of the
world. Like those in HTLV-1, the mechanisms that account for a high degree of genomic stability
for BLV may be the result of restrictions on replication in vivo, a highly cell-associated trans-
mission mode, and the dependence on clonal expansion of infected lymphocytes for genomic
replication.
BLV AND HTLV-1 GENE PRODUCTS AND THEIR ROLE IN PATHOGENESIS

Like all retroviruses, the outcome of BLV and HTLV-1 infection depends upon the complex
interplay between viral proteins that mediate virus replication and host cell pathways vital to the
survival of host (Figure 3). The BLV and HTLV-1 Gag proteins (so called because they represent
group-specific antigens) are produced as single-precursor polyproteins that are myristylated to
allow targeting to the inner lipid of the cell plasma membrane. At this location, or soon after
budding, the precursor is cleaved by viral-encoded proteases to produce the final MA, CA, and
NC functional units. For both viruses, CA units multimerize to form the inner core of the virus
particle, whereas NC interacts with the genomic RNA. Domains within MA, such as PPPY for
HTLV-1, interact with host cell proteins, such as Nedd4.1 and Tsg101, to promote virus
budding from cell membranes (31). It is also clear that MA likely is important for cell-to-cell

Figure 3
Retrovirus replication cycle, receptor engagement through assembly of new virions. Key steps following
uncoating of the virus particle include reverse transcription and production of DNA intermediate from the
RNA genome. Following transport to the nucleus and integration, viral transcripts produce key regulatory
and structural gene products. Virion assembly precedes budding from the host cell as fully formed virus
particles or cell-to-cell transmission.
transmission of HTLV-1 through interaction with host cell kinases (32, 33). HTLV-1 uses
a C-terminal peptide region of NC to block the action of the host-restriction factor ABOBEC3G
(34). Both BLV- and HTLV-1-encoded proteases are produced from ribosomal frame shifting,
are initially inactive in their precursor forms, and become active only upon virus budding.
Likewise, reverse transcriptase and integrase are produced following cleavage of the Gag/Pol
precursor polyprotein.
Proteolytic cleavage of the BLV Gag precursor (Pr44gag) is mediated by a virally encoded
protease, resulting in BLV Gag proteins (MA, CA, and NC). BLV protease is synthesized from
a gag-protease precursor (pr66gag-prt) via a frame-shift suppression of the gag-termination
codon (35). Despite their evolutionary relationship, the BLV and HTLV proteases have
unique cleavage-recognition sites. The BLV NC (12 kDa) is proline rich and bound tightly to the
packaged genomic RNA in a zinc-dependent manner (36). BLV CA, a 24 kDa protein like
HTLV-1 CA p24, forms the greatest component of the virion capsid and a major target of the
host immune response. BLV CA contains T cell epitopes and a major homology region required
for infectivity. Antibody- and antigen-recognition studies support the conserved nature of CA
between BLV and HTLV-1.
The BLV pol gene, like that of HTLV-1, is translated after a ribosomal frame shift to produce
reverse transcriptase, which is responsible for converting the RNA genome into the double-
196 Lairmore
stranded DNA intermediate that will integrate into the host cell genome. Interestingly, BLV reverse
transcriptase has a higher fidelity rate compared with other retroviruses, including HIV-1 (37).
Unintegrated viral DNA copies are relatively common in asymptomatic and persistently lym-
phocytosis cattle, but the extra role these genomic forms play in the pathogenesis of lymphoma or
leukemia is unclear, as they are rare in fully transformed cells (38).
HTLV-1 Env is well conserved among isolates and is synthesized as a polyprotein precursor
(gp62), which is subsequently glycosylated and cleaved into two proteins, SU gp46 and TM gp21
(39). SU is required for entry into the target cell by mediating specific attachment to cellular
receptors, whereas the TM functions in fusion between viral and cellular membranes to allow viral
entry. The HTLV-1 C terminus is highly antigenic and recognized by serum antibodies from
approximately 95% of HTLV-1-infected individuals. Specific protein motifs of HTLV-1 Env have
been defined in terms of their ability to interact with cellular proteins important in cell fusion
events (reviewed in References 39, 40). For example, the HTLV-1 TM contains YSLI amino acid
sequences that represent consensus YXXP motifs, known to interact with cellular adaptor protein
complexes, and a PDZ-binding motif (ESSL) at the C terminus of Env.
The mechanism of action that facilitates cell-to-cell transmission of the BLV and HTLV-1 is an
active area of investigation (Figure 4). Recent studies of HTLV-1 have three key cellular proteins
that influence binding and fusion of the virus. The glucose transporter (GLUT-1) is involved in
envelope-mediated cell-to-cell fusion and is assisted by heparin sulfate proteoglycan, which binds
virus particles on cell surfaces and facilitates entry (39). The cellular protein neuropilin-1 has also
been implicated as a binding partner of Env in certain cell types and when ectopically expressed can
increase HTLV-1-mediated syncytium formation (41).
The BLV envelope gene is transcribed as a 5.1-kb mRNA and encodes for a 72-KDa precursor.
Although overall the BLV and HTLV envelopes show only approximately 30% amino acid
identity, they exhibit similar functional properties. The BLV precursor is cleaved into two subunits
and glycosylated, resulting in an extracellular p51 (SU) and the transmembrane p30 (TM) pro-
teins, which are associated with each other through disulfide bonds (42). BLV SU elicits specific
antibodies in infected animals, which are useful for diagnostic tests and in the creation of potential
vaccines (16). Like HTLV-1 SU, BLV gp51 oligomerizes to form the putative receptor-binding
domain that binds a putative receptor, a subunit of adaptor-related protein complex AP3 involved
in intracellular vesicle transport (43).
Like HTLV-1, BLV is most efficiently transmitted in a cell-associated manner, likely owing to
the complex interaction of the viral envelope and cell membrane receptors. The BLV TM acts as
a fusion protein and inserts in cell membranes. It also acts in signal transduction through immu-
noreceptor tyrosine-based activation motifs to transduce signals through the cell membranes, is
required for infectivity in vivo (44), and contains typical proline-rich motifs (PXXP) important for
the maintenance of typical viral loads in vivo (45). In addition, BLV TM interacts with phosphatase
SHP-1 and acts as a critical negative regulator of B cell receptor signaling (46, 47).
A common regulatory protein of both BLV and HTLV is the transcriptional activator protein
of the X genome region, Tax. For HTLV-1, Tax is a 40-kDa phosphoprotein translated from
a doubly spliced mRNA from the ORF IV (reviewed in Reference 48). Both BLV Tax and HTLV-1
Tax are predominantly nuclear proteins that can translocate to the cytoplasm through use of
a nuclear export protein. For each virus, Tax initiates viral transactivation from the LTR of the
integrated provirus by binding unique sites in the U3 region of the LTR. Much more is known
about HTLV-1 Tax. From the TRE-1, HTLV-1 Tax stabilizes CREB/ATF (activator of tran-
scriptional factors) dimers required for viral gene expression but can also recruit and bind CBP/
p300 (19). The ability of Tax to recruit and stabilize CREB-CBP/p300 and other factors, such as
P/CAF (CBP/p300-associated factor), promotes transcription of the provirus. Importantly, BLV

Infected Uninfected
lymphocyte lymphocyte
Provirus
Formation
of virological Lymphocyte
synapse division and clonal
expansion
Viral RNA
preintegration
fragment
Newly infected
lymphocyte
Figure 4
Cell-to-cell transmission of deltaretroviruses. Lymphocytes are infected with provirus upon cell activation and
formation of viral synapse with uninfected lymphocyte, followed by transfer of a partially assembled virus
particle. Infected lymphocytes with fully integrated provirus upon cell division replicate viral genome, referred
to as clonal expansion.
and HTLV-1 Tax can also activate expression of cellular genes. For HTLV-1, these include key
cellular signaling pathways that influence cytokine production driving lymphocyte proliferation.
The transforming ability of Tax is most likely attributable to its influence over the expression of
these important cellular genes.
The importance of BLV Tax in virus infectivity in vivo has been demonstrated using molecular
clones of the virus that have selective deletions of pX tax ORF that delay the onset of tumors in the
sheep model (49, 50). Like HTLV-1 Tax, BLV Tax is a phosphoprotein and requires the co-
operation of cellular factors to activate transcription. BLV Tax contains zinc finger and leucine-
rich activation domains that, if deleted, eliminate transactivation activity. BLV Tax, like HTLV-1
Tax, can cooperate with the Ha-ras oncogene to transform cells in culture and form tumors in
immunodeficient mice. BLV Tax expression in primary ovine B cells initially depends on CD154
and interleukin-4 but leads eventually to cytokine-independent growth (51). Immortalization of
B cells mediated by BLV Tax results in enhanced Bcl-2 protein levels and nuclear accumulation of
NFkB (52). Similar to HTLV-1 Tax, BLV Tax also inhibits DNA repair, resulting in the accu-
mulation of mutations in cellular DNA.
The mechanisms responsible for the development of lymphoma and leukemia associated with
BLV and HTLV-1 have been investigated intensely since each virus was associated with disease.
Many events at the molecular and biological level have been revealed that shed light on how these
198 Lairmore
viruses cause cancer (Figure 5). For each, the role of Tax is likely a critical factor in setting the stage
for cell transformation. HTLV-1 Tax causes the translocation of NFkB, resulting in the activation
of gene pathways that promote lymphocyte proliferation or alter cell survival. HTLV-1 Tax binds
p50, p52, p65, and c-Rel NFkB family members and also IkBa, an inhibitor of NFkB nuclear
translocation (53–57). The association of Tax and IkBa destabilizes the IkBa/b/g-NFkB complex
and allows for NFkB translocation. Thus, by targeting NFkB, the virus activates prosurvival and
antiapoptotic genes, enhancing cell survival.
HTLV-1 Rex is a 27-kDa phosphoprotein encoded by pX ORF III, which contains an RNA-
binding domain, nuclear localization and export sequences, and a multimerization domain
(8, 58, 59). Rex acts posttranscriptionally to facilitate nuclear transport of unspliced and singly
spliced viral RNAs to the cytoplasm favoring structural gene translation and viral proteins
required for assembly. The common element in the U3/R30 LTR, RxRE, allows Rex to bind all
viral-encoded RNAs. HTLV-1 Rex plays an essential role in viral infectivity but does not appear
to contribute to transforming tropism preferences (60). BLV Rex contains structural and
functional features similar to those of HTLV-1 Rex. BLV Rex exhibits a defined nuclear lo-
calization and has a nuclear export signal, as well as a central leucine-rich activation domain and
amino-terminal arginine-rich motifs required for RNA-binding and nuclear localization. In-
terestingly, HTLV-1 and BLV Rex are interchangeable for the function of posttranscriptional
regulation.
Leukemia
Transformed lymphocytes
Lymphoma
• Frequent loss of Tax expression
• Continuous expression of the
HBZ gene (HTLV-1)
Growth promotion
• Tax CTL
• Other viral genes
ions
a l t erat nges
Infected cells ic ha
So mat tional c As)
RN
are essential for scrip icro
transmission Tran enes, m
(g
Cell-cell Clon
transmission al p
roli
fera
tion
Suppression of proliferation
• Cytotoxic T cells against Tax
• Tax expression
• Decreased expression mediated,
e.g., HBZ and p30 (HTLV-1) Proliferating infected cells
• Role for BLV G4/R3?
• HTLV-associated diseases
(HAM/TSP, uveitis)
• BLV-persistant lymphocytosis
Figure 5
Bovine leukemia virus (BLV)- and human T-lymphotrophic virus type-1 (HTLV-1)-mediated cell proliferation and transformation.
Following cell-to-cell transmission, cell fate is determined by balance between immune recognition (e.g., cytotoxic T cells), virus-mediated
cell proliferation (e.g., Tax-mediated), and control of virus expression (e.g., HTLV-1 p30). Eventual selection and immortalization are
followed by clonal transformation and lymphoma (rarely after prolonged period of infection) or cell survival and proliferation, leading to
lymphocytosis (BLV) or immune-mediated disorders [e.g., HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
associated with HTLV-1].

Additional nonstructural gene products from the pX region of the BLV and HTLV-1 genome
have essential roles in the replication and transmission of each virus (Figure 1 and 2). In the case of
HTLV-1, alternative splicing of ORF I and II yields mRNAs that encode for p27, p12, p30, and
p13. The nonstructural genes encoded from ORFs I and II are vital for viral infectivity, main-
tenance of the virus life cycle, and proviral loads in vivo, as well as host cell activation and
regulation of viral gene transcription (58). The genes from ORF I and II can be detected in HTLV-1-
positive cell lines and in patients, but detection of the actual proteins has been difficult owing to the
low amounts that are expressed (reviewed in Reference 61). HTLV-1-infected patients produce
antibodies and cytotoxic T cells directed against these proteins, as well as structural and other
regulatory proteins, such as Tax (12, 62, 63).
HTLV-1 ORF I encodes for p12, a 99–amino acid hydrophobic rich protein with two putative
transmembrane domains and two leucine zipper motifs (64–66). The protein localizes to the
endoplasmic reticulum and also has proline-rich Src homology-3 motifs. The conserved PSLP(I/L)T
motif is homologous to the calcineurin-binding PxIxIT motif present in nuclear factor of ac-
tivated T cells, which has the capacity for calcineurin binding and influences calcium signaling
(reviewed in Reference 61). Proteolytic processing of HTLV-1 p12 results in the production of
a smaller 8 KD, which acts to increase T cell contact through LFA-1 but apparently diminishes
T cell activation by inhibiting proximal T cell receptor signaling at the immunological synapse
(67). Importantly, HTLV-1 pX ORF I is important for viral transmission in the rabbit and
a primate model (8).
HTLV-1 pX ORF II encodes for p13, a protein that is predominantly localized in the nucleus
and mitochondria of transfected cells and that, when overexpressed, alters the inner membrane
potential of mitochondria. Although the exact role for the protein is unclear, p13 may influence
cell proliferation or survival depending on the stage of cell transformation (68). An infectious
molecular clone of HTLV-1 with a selective mutation that prevents the translation of p13, without
affecting RNA splicing, failed to establish viral infection in a rabbit model, indicating an essential
role in virus transmission and persistence (69). Interestingly, p13 binds with farnesyl pyro-
phosphate synthase, which is involved with synthesis of substrates required for prenylation and
subsequent activation of Ras (70). This function is similar to the action of a BLV G4.
HTLV-1 p30 expressed mostly in the cell nucleus and nucleolus exhibits transcriptional and
posttranscriptional activity (8). The protein influences viral gene expression posttranscriptionally
by binding Tax/Rex mRNA in the nucleus and preventing its exit into the cytoplasm for trans-
lation. p30 causes a delay at the G2-M phase of the cell cycle and acts in a prosurvival mode in the
face of genotypic mutations induced by HTLV-1 replication and Tax expression (71). Ectopically
expressed p30 binds to cellular ataxia-telangiectasia mutated (ATM) and REGg (a nuclear 20S
proteasome activator) (72). In conditions of genotoxic stress, p30 expression appears to reduce
levels of ATM and increase cell survival, suggesting a role in viral spread. p30 also binds with the
Myc-Tip60 complex, modifies transcription, and may promote cellular transformation (73).
Finally, HTLV-1 p30 inhibits conservative homologous DNA repair by targeting the MRN
complex, favoring DNA repair that may contribute to cell transformation (74). HTLV-1 mo-
lecular clones that lack p30 expression do not establish infection in a rabbit model of HTLV-1
infection (75, 76).
HTLV-1 expresses two mRNA products from the 30 LTR of the complementary strand of the
virus genome. The protein produced from these antisense transcripts has been named HTLV-1
bZIP factor, or HBZ (77). However, deletion of HBZ expression from infectious molecular clones
of HTLV-1 results in decreased proviral load and antibody responses in the rabbit model, and
knockdown of HBZ expression reduces tumor growth in a mouse model of ATL (78). HTLV-1
HBZ expression interferes with Tax-mediated viral transactivation and appears to act as a negative
200 Lairmore
regulator of viral transcription. This unique protein interacts with JunD, JunB, and c-Jun and,
depending on the context, may enhance or reduce transcriptional activity (79–82). Further studies
will be required to identify the role of HBZ in the context of the HTLV-1 replication cycle and in the
pathogenesis of HTLV-1-mediated diseases.
An interesting parallel between HTLV-1 and BLV is the expression of nonstructural proteins
that influence virus–host cell interactions. BLV contains the R3 and G4 open ORFs in a region
between the envelope and the tax/rex genes (23, 24, 83, 84). The R3 mRNA is bicistronically
produced by differential splicing, whereas G4 mRNA contains only one intron located between an
unusual splice donor site at position 502 (instead of 305 for the other viral mRNAs). When
translated, these mRNAs produce proteins of 5.5 kDa and 11.6 kDa for R3 and G4, respectively.
BLV R3 is targeted to the nucleolus and binds RNA, and it may influence posttranscriptional
regulation of viral expression. In contrast, G4, like HTLV-1 p13, is localized both in the nucleus
and in mitochondria. When ectopically expressed, BLV G4 promotes primary rat embryo
fibroblasts to become immortalized. Similar to HTLV-1 p13, G4 binds farnesyl pyrophosphate

synthetase, a protein involved in the mevalonate/squalene pathway and in synthesis of FPP, a
substrate required for prenylation of Ras. R3 and G4 are essential to effect viral replication and the
pathogenic effects of BLV in the sheep model (24).
HOST IMMUNE RESPONSES IN HTLV-1 AND BLV CONTROL AND

PATHOGENESIS OF DISEASE
Following HTLV-1 and BLV infection, virus-specific antibodies can be detected in the infected
individual within the first weeks by most assays and typically persist throughout these lifelong
retroviral infections. In the case of BLV infections in cattle, antibodies are produced to react with
most structural viral proteins but are particularly strong against viral envelope (gp51) and CA
proteins (p24) (16). In addition, like HTLV-1 infections, antibodies can be directed at non-
structural and regulatory proteins, such as Tax.
The antibody response of BLV-infected cattle persists throughout the lifetime of the infected
animal, but eventually the cytotoxic (CTL) and helper T cell responses may diminish over time,
leaving these animals more susceptible to infection by opportunistic pathogens (16, 85, 86). In
cattle, gd T lymphocytes comprise a substantial portion of the CTL response. The transmission of
BLV, like that of HTLV-1, is highly cell dependent; thus, natural or iatrogenic routes of trans-
mission regularly result from the transfer of infected cells. In cattle, BLV transmission has been
associated with trauma, restraint devices, gloves used for rectal examination, reuse of needles and
surgical instruments, and, rarely, insects acting as mechanical vectors. Typically, less than 10% of
calves born to infected dams are BLV positive at birth, but over time, calves typically acquire the
infection from exposure to maternal lymphocytes.
Programs of test and removal have been effective at eliminating BLV from infected herds of
cattle (9, 87–89). The length of time required to obtain a virus-free herd varies, depending on the
initial prevalence of infection. To be effective, these programs must isolate calves from infected
mothers and periodically retest. Similar to many retroviral infections, vaccination against BLV
infection has not been shown to be effective at preventing the infection (6). Limited evidence
suggests that experimental inactivated vaccine may prevent disease following virus challenge, but
this practice has not been implemented and is not cost effective.
Unlike BLV, which targets B cells, HTLV-1 infects and persists in memory CD4þ T cells that,
when activated, induce viral transcription. Both viruses depend upon low levels of transcription
and clonal expansion of their target cells for persistence in the face of an active immune response.
Both viruses also depend upon a highly regulated control of viral protein expression, and for both

viruses, the number of cells carrying the provirus far exceeds those expressing viral mRNA. Based
on epidemiologic studies, it appears that HTLV-1 infection acquired from transfusion of infected
blood or blood products favors the development of inflammatory disease associated with HTLV-1,
whereas exposure from breastfeeding has been linked to the development of lymphoma and
leukemia (reviewed in Reference 8). These studies suggest that host immune-recognition deter-
minants control the level of virus replication in infected individuals and hence the formation of
detrimental immune reactions against the virus infection. Cell-mediated immune responses against
HTLV-1 Tax, as well as structural and other nonstructural proteins, persist throughout the life of
an infected individual (12, 63, 90). In patients with HAM/TSP, these responses can be quite robust
and are believed to contribute to the pathogenesis of this disorder. In addition, HAM/TSP patients
maintain elevated levels of proinflammatory cytokines, which are believed to promote tissue
injury. Although a vigorous antibody response can be demonstrated to promote neutralizing
capabilities, the role the antibodies play in the protection or pathogenesis of HTLV-1-associated
diseases is unclear.
Lymphoma associated with BLV infection and HTLV-1-associated ATL are examples of how
persistent viruses are linked to multistage carcinogenesis processes (Figure 5). For both viral
infections, the constant immunological pressure exerted by the host selects for surviving cells with
genetic alterations in proviral DNA and nearby somatic host DNA that favor controlled viral
expression and cell survival. Eventually, cell clones arise that retain their ability to proliferate and
become fully transformed.
ANIMAL MODELS FOR BLV AND HTLV-1 INFECTION AND DISEASE

Animal models of BLV and HTLV-1 transmission and spread have provided fundamental in-
formation about viral and host determinants of infection (2, 58, 91–93). Rabbits are a consistent
species to model HTLV-1 infection in humans, as was first reported using intravenous inoculations
of the transformed T cell lines from human and rabbit sources. Early studies verified routes of
transmission (e.g., blood) for the virus infection (reviewed in Reference 58). These studies provided
accurate data to estimate the number of cells capable of transmitting the virus infection and
effective measures to prevent transmission of the virus.
Infectious molecular clones of HTLV-1 were instrumental to identify viral determinants that
control infection and demonstrated the requirement of accessory and regulatory proteins of the
virus in the maintenance of proviral loads (69, 74, 94–99). HTLV-1 was found to accumulate in
primary lymphoid and gut-associated lymphoid compartments in rabbits and was associated with
an early lymphocytosis (99). These data are consistent with emerging evidence that HTLV-1
promotes lymphocyte proliferation, thereby enhancing early viral spread. Cyclosporine treatment
prior to HTLV-1 infection in the rabbit model promoted enhanced viral expression, indicating that
immunologic control is a key determinant of viral persistence (100).
Mouse models of HTLV-1-associated lymphoma often use xenografts to test anticancer com-
pounds or transgenic mice and have been reviewed recently (92). Attempts to transmit HTLV-1 in
mice have produced inconsistent infections with limited virus expression in tissues. A nonhuman
primate model has been developed to test immune responses against the infection, as well as
potential HTLV-1 vaccines (101, 102). Mutant HTLV-1 molecular clones have demonstrated the
key role of dendritic cells in viral transmission in rabbits and macaques (103). Rat models of
HTLV-1 infection have been used to test the role of cell-mediated immunity to the infection but
appear to be less reproducible compared with other models. Experimental infection of Wistar-
King-Aptekman-Hokudai rats mimics the neurodegenerative disease associated with HTLV-1
infection but lacks key histologic features of the disease (104).
202 Lairmore
Animal models of BLV transmission have been developed in rodents, rabbits, and small
ruminants, such as sheep. Sheep represent a productive animal model for both ease of transmission
and reduced time period to disease outcomes (10, 17–18, 105, 106). Sheep infected with natural
BLV isolates and molecular clones of the virus have been used to investigate the pathogenesis of the
virus, potential treatments to ablate tumors, and vaccines against the infection. Like HTLV-1, the
development of tumors in BLV-infected sheep depends on a functional tax gene but is influenced
by other regulatory genes. Molecular clones of BLV that contain deletions that prevent R3/G4
expression reduce the transmission of BLV and limit the ability of the virus to cause lymphoma in
infected sheep. These results parallel data from HTLV-1 molecular clones with deletions in pX
ORF I and II.
The use of molecular clones of BLV provides clear evidence for the importance of the 50
LTR cyclic-AMP responsive (CRE) site for LTR activity and in maintaining proviral loads in
infected sheep (16). Epigenetic modification, such as histone acetylation and methylation,
allows BLV to remain relatively transcriptionally silent, which helps the virus maintain
persistence. In parallel, the BLV sheep model provided evidence that enhanced LTR activity
was detrimental to viral loads, creating a potential avenue for therapeutic interventions that
enhance viral expression and immune elimination. Although an attractive theory, when tested
in the sheep model, this approach unfortunately proved to be an ineffective treatment to
eliminate the infection.
SUMMARY AND FUTURE PROSPECTS

As complex deltaretroviruses, BLV and HTLV-1 share not only genomic similarities but also
common modes of transmission and a similar pathogenesis. Whereas much more is known about
HTLV-1 in terms of molecular details of virus spread, much can be learned from BLV from animal
models that develop lymphoma. Each virus has evolved to spread from mother to offspring
through breast milk as an efficient way to maintain the virus within an infected population. Both
viruses complicate medical and veterinary procedures through their transmission via blood
transfusion or from contaminated instruments. HTLV-1 is associated with an aggressive form of
T cell ATL and a variety of lymphocyte-mediated disorders, such as HAM/TSP. BLV, in contrast,
targets B cells for transformation and is primarily associated with lymphocytosis and a multi-
centric lymphoma in adult dairy cattle. Both complex retroviruses contain typical gag, pol, and
env genes but also contain unique, nonstructural proteins encoded from the pX region that are
essential for viral spread in vivo. Infectious molecular clones of these viruses have allowed testing
of viral genes in the transmission and spread of the virus. These studies have provided important
insights into the role of nonstructural proteins in maintaining viral loads and transmission.
Further studies of specific functional motifs of key viral gene products in relation to mucosal
transmission are needed to determine the interplay of host defenses and viral determinants in the
viral transmission and spread of each virus.
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
I thank Mr. Richard Hayes for illustrations.

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Annual Review of
Animal Biosciences
Volume 2, 2014 Contents

From Germ Cell Preservation to Regenerative Medicine: An Exciting

Research Career in Biotechnology

Ian Wilmut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Genomic Imprinting in Farm Animals
Xiuchun (Cindy) Tian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Recent Advances in Primate Phylogenomics
Jill Pecon-Slattery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Domestication Genomics: Evidence from Animals
Guo-Dong Wang, Hai-Bing Xie, Min-Sheng Peng, David Irwin,
and Ya-Ping Zhang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Behavior Genetics and the Domestication of Animals
Per Jensen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Applied Animal Genomics: Results from the Field
Alison L. Van Eenennaam, Kent A. Weigel, Amy E. Young,
Matthew A. Cleveland, and Jack C.M. Dekkers . . . . . . . . . . . . . . . . . . . . 105
Pestiviruses
Matthias Schweizer and Ernst Peterhans . . . . . . . . . . . . . . . . . . . . . . . . . 141
Pathogenesis and Molecular Biology of a Transmissible Tumor in the
Tasmanian Devil
Hannah S. Bender, Jennifer A. Marshall Graves, and Janine E. Deakin . . . 165
Animal Models of Bovine Leukemia Virus and Human T-Lymphotrophic
Virus Type-1: Insights in Transmission and Pathogenesis
Michael D. Lairmore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Malignant Catarrhal Fever: Inching Toward Understanding
Hong Li, Cristina W. Cunha, Naomi S. Taus, and Donald P. Knowles . . . 209
vi
Comparative Immune Systems in Animals
Shaochun Yuan, Xin Tao, Shengfeng Huang, Shangwu Chen,
and Anlong Xu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Origin and Evolution of Adaptive Immunity
Thomas Boehm and Jeremy B. Swann . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
The Functional Significance of Cattle Major Histocompatibility Complex
Class I Genetic Diversity
Shirley A. Ellis and John A. Hammond . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Incidence of Abnormal Offspring from Cloning and Other Assisted
Reproductive Technologies
Jonathan R. Hill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Preadipocyte and Adipose Tissue Differentiation in Meat Animals:
Influence of Species and Anatomical Location
G.J. Hausman, U. Basu, S. Wei, D.B. Hausman, and M.V. Dodson . . . . . 323
Serotonin: A Local Regulator in the Mammary Gland Epithelium
Nelson D. Horseman and Robert J. Collier . . . . . . . . . . . . . . . . . . . . . . . 353
Evolution of the Modern Broiler and Feed Efficiency
Paul B. Siegel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Amino Acid Nutrition in Animals: Protein Synthesis and Beyond
Guoyao Wu, Fuller W. Bazer, Zhaolai Dai, Defa Li, Junjun Wang,
and Zhenlong Wu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
The Suckling Piglet as an Agrimedical Model for the Study of Pediatric
Nutrition and Metabolism
Jack Odle, Xi Lin, Sheila K. Jacobi, Sung Woo Kim,
and Chad H. Stahl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Cattle Production Systems: Ecology of Existing and Emerging
Escherichia coli Types Related to Foodborne Illness
David R. Smith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
Gastrointestinal Tract Microbiota and Probiotics in Production Animals
Carl J. Yeoman and Bryan A. White . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Biodiversity of Cone Snails and Other Venomous Marine Gastropods:
Evolutionary Success Through Neuropharmacology
Baldomero M. Olivera, Patrice Showers Corneli, Maren Watkins,
and Alexander Fedosov . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Ecological Risk Analysis and Genetically Modified Salmon: Management
in the Face of Uncertainty
Darek T.R. Moreau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Contents vii
The Modern Feedlot for Finishing Cattle
John J. Wagner, Shawn L. Archibeque, and Dillon M. Feuz . . . . . . . . . . . 535
The Nexus of Environmental Quality and Livestock Welfare
Sara E. Place and Frank M. Mitloehner . . . . . . . . . . . . . . . . . . . . . . . . . . 555
Errata
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be found at http://www.annualreviews.org/errata/animal
viii Contents
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Annual Review of Statistics and Its Application
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Editor: Stephen E. Fienberg, Carnegie Mellon University

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ANNUAL

REVIEWS Further Animal Models of Bovine

• Top cited articles

• Top downloaded articles

Annu. Rev. Anim. Biosci. 2014. 2:189–208 Keywords

Discovery, Transmission, and Current Epidemiology

DISEASE ASSOCIATIONS AND COMMON CLINICAL FEATURES

HTLV-1-associated ATL can express in several clinical presentations but is characterized by

www.annualreviews.org Animal Models of BLV and HTLV-1 191

Etiologic Lymphoma/phenotype Neoplastic clinical presentation

jaundice, weight loss, and

VIRAL GENOME AND TRANSCRIPTIONAL MAP

R U5 gag pro pol env pX U3 R

4,641 4,831 6,478

4,641 4,831 6,950

R U5 gag pro pol env pX U3 R

5,186 7,270 8,870

www.annualreviews.org Animal Models of BLV and HTLV-1 193

1 305 4,649 4,871 7,018

1 305 4,649 4,871 7,247

BLV AND HTLV-1 GENE PRODUCTS AND THEIR ROLE IN PATHOGENESIS

www.annualreviews.org Animal Models of BLV and HTLV-1 195

www.annualreviews.org Animal Models of BLV and HTLV-1 197

www.annualreviews.org Animal Models of BLV and HTLV-1 199

fibroblasts to become immortalized. Similar to HTLV-1 p13, G4 binds farnesyl pyrophosphate

HOST IMMUNE RESPONSES IN HTLV-1 AND BLV CONTROL AND

www.annualreviews.org Animal Models of BLV and HTLV-1 201

ANIMAL MODELS FOR BLV AND HTLV-1 INFECTION AND DISEASE

SUMMARY AND FUTURE PROSPECTS

www.annualreviews.org Animal Models of BLV and HTLV-1 203

7. Watanabe T. 2011. Current status of HTLV-1 infection. Int. J. Hematol. 94:430–34

www.annualreviews.org Animal Models of BLV and HTLV-1 205

www.annualreviews.org Animal Models of BLV and HTLV-1 207

Volume 2, 2014 Contents

From Germ Cell Preservation to Regenerative Medicine: An Exciting

Research Career in Biotechnology

Jonathan R. Hill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

An online log of corrections to Annual Review of Animal Biosciences articles may

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Editor: Stephen E. Fienberg, Carnegie Mellon University

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