STLV-1 as a model for studying HTLV-1 infection

Abstract

Abstract Few years after HTLV-1 identification and isolation in humans, STLV-1, its simian counterpart, was discovered. It then became clear that STLV-1 is present almost in all simian species. Subsequent molecular epidemiology studies demonstrated that, apart from HTLV-1 subtype A, all human subtypes have a simian homolog. As HTLV-1, STLV-1 is the etiological agent of ATL, while no case of TSP/HAM has been described. Given its similarities with HTLV-1, STLV-1 represents a unique tool used for performing clinical studies, vaccine studies as well as basic science.

Full text

Jégadoetal. Retrovirology (2019) 16:41
https://doi.org/10.1186/s12977-019-0503-0
REVIEW
STLV-1 asamodel forstudying HTLV-1
infection
Brice Jégado1, Fatah Kashanchi2, Hélène Dutartre1 and Renaud Mahieux1*
Abstract
Few years after HTLV-1 identification and isolation in humans, STLV-1, its simian counterpart, was discovered. It then
became clear that STLV-1 is present almost in all simian species. Subsequent molecular epidemiology studies dem-
onstrated that, apart from HTLV-1 subtype A, all human subtypes have a simian homolog. As HTLV-1, STLV-1 is the
etiological agent of ATL, while no case of TSP/HAM has been described. Given its similarities with HTLV-1, STLV-1 repre-
sents a unique tool used for performing clinical studies, vaccine studies as well as basic science.
Keywords: HTLV-1, STLV-1, ATL, Prevalence, Interspecies transmission, Animal model, Therapy
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Background
e first human oncogenic retrovirus was discovered in the
USA, in a T cell line obtained from blood cells of a patient
suffering from a disease then called “cutaneous T-cell lym-
phoma” [1, 2]. Few years earlier, Adult T-cell Leukemia/
Lymphoma or ATLL (i.e. an aggressive malignancy of
CD4+ T-cells) had been described in Japan [3, 4]. In 1982,
Japanese researchers also reported the presence of a ret-
rovirus among ATLL patients. ey named it Adult T cell
leukemia virus (ATLV). Further work demonstrated that
HTLV-1 specific antibodies were present among Japa-
nese ATLL patients, thus allowing identification of the first
HTLV-1 endemic area [5]. Later, it was decided to name this
virus HTLV-1 for Human T-cell Leukemia Virus type 1.
Few years later, Tropical Spastic Paraparesis/HTLV-1
associated myelopathy (TSP/HAM), a severe neuromy-
elopathy, was also identified as another disease caused
by HTLV-1 [6]. us, ATLL and TSP/HAM are the main
pathologies present among HTLV-1 infected individu-
als. It was recently estimated that 5 to 10 million people
are infected by HTLV-1 worldwide, although HTLV-1
prevalence is likely to be underestimated. Two to 4%
of HTLV-1 carriers will develop either ATLL or TSP/
HAM, while most of them will remain asymptomatic
[7]. HTLV-1 is endemic in areas such as Japan, central
Africa, the Caribbean region and South America [8].
Because HTLV-1 mostly replicates through clonal expan-
sion of infected cells even in asymptomatic carriers [9],
its retroviral genome displays a remarkable genetic stabil-
ity. HTLV-1 molecular epidemiology studies have been
carried out throughout the world. e very low genetic
variability allowed identification of different HTLV-1
subtypes. All but one of these subtypes, i.e. Cosmopoli-
tan subtype A that is present all over the world, are spe-
cific to a given African or Asian region [8]. ATL cases
were described in HTLV-1 carriers infected by HTLV-1
subtype A but also subtype B and subtype C [10, 11],
thus suggesting that ATL occurrence is not linked to the
most frequent HTLV-1 subtype. Of note, HTLV-1 sub-
type B and subtype C lack p12 and/or p30 auxiliary pro-
tein. Whether the lower ATL frequency in type B and C
infected individuals is linked to the absence of these pro-
teins remains to be determined.
In 1982, lymphocytes from a Japanese monkey
(Macaca fuscata) were co-cultured with chronically and
productively infected T-cells from the MT-2 cells, an
HTLV-1-transformed cell line. is allowed the authors
to obtain a simian cell line persistently infected by
Open Access
Retrovirology
*Correspondence: renaud.mahieux@ens-lyon.fr
1 International Center for Research in Infectiology, Retroviral Oncogenesis
Laboratory, INSERM U1111 - Université Claude Bernard Lyon 1, CNRS,
UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Fondation
pour la Recherche Médicale, Labex Ecofect, Lyon, France
Full list of author information is available at the end of the article

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Jégadoetal. Retrovirology (2019) 16:41
HTLV-1, thus suggesting that Japanese monkeys might
be susceptible to HTLV-1 natural infection [12]. Later,
seroepidemiological studies were performed in Japan
and demonstrated that many Japanese monkeys were
infected by HTLV-1-like viruses [13]. Sera from New
World Monkeys (NWM), Old World Monkeys (OWM)
and Apes were then tested and revealed the presence
of antibodies reacting against HTLV-1 antigens. Such
antibodies were detected in OWM and Apes, but not
in NWM, suggesting endemicity of HTLV-1-related
viruses in African and Asian monkeys, but not in Ameri-
can animals [14]. Sequence analyses characterized these
viruses as Simian T-cell Leukemia Viruses (STLVs) [15,
16]. To date, it is well established that Old World Non-
Human Primates (NHPs) and Apes are naturally infected
with a great variety of STLV-1 viruses and that HTLV-1
appeared in Humans following STLV-1 cross-species
transmission approximately 27,300 years ago (95% CI
19,100–35,500) in Africa, even if interspecies transmis-
sion episodes still occur [17–19]. Given the high degree
of similarity between HTLV-1 and STLV-1 sequences, it
was suggested to cluster these viruses in the single PTLV
(Primate T lymphotropic virus) family [20–22]. Because
STLV-1 induces ATLL in naturally infected NHPs [23,
24], and even if some auxiliary proteins are lacking [25],
it represents a suitable tool that contributes to our under-
standing of HTLV-1 pathogenesis. is review will com-
pare HTLV-1 and STLV-1 retroviruses from different
aspects and will focus on the use of STLV-1 as a model of
HTLV-1 infection.
STLV‑1 epidemiology
Around 132 non-human primate species represent Old
World Monkeys (OWM). ey are divided in two sub-
families, Cercopithecinae and Colobinae, distributed in
African and Asian continents [26].
To determine which simian species carry STLV-1,
seroepidemiological studies were performed using kits
that had been previously developed for the detection
of anti-HTLV-1 human antibodies, as well as by PCR
(Fig. 1). Sera from Japanese monkeys were tested, and
25% scored seropositive. As in humans, STLV-1 inci-
dence increased with age and was higher in females than
males. Other species were tested later. A high seropreva-
lence was observed in African Green monkeys (AGM).
Two studies then reported STLV-1 infection in captive
Old World NHPs and Apes [27, 28]. Ishikawa etal. [29]
performed an STLV-1 survey using 567 NHPs’ blood
samples covering 30 species caught in the wild or kept
in zoos, institutes or private owners from Kenya, Gabon,
Ghana, Cameroon, Ethiopia and Indonesia. STLV-1 was
detected in African Green monkeys and Sykes’ monkeys,
in Olive baboons, Patas monkeys, Mandrills and Gorillas.
STLV-1 was also found in different species of macaques
from Indonesia, with a seroprevalence ranging from 11
to 25%. Other studies reported natural STLV-1 infec-
tions in AGM, Vervet monkeys and among baboon spe-
cies (Papio anubis, Papio hamadryas, Papio papio and
Papio cynocephalus) originating from South Africa and
Ethiopia [30–33]. As in Japan, the infection status posi-
tively correlates with age, and disease incidence is higher
in females than males. Other seroepidemiological stud-
ies were also performed [34–44] (Fig.1). irty-one Old
World NHP species were reported as naturally infected
with STLV-1 [33, 45–50].
STLV-1 sequence analyses were then performed in
order to determine relationship between STLV-1 and
HTLV-1 and whether HTLV-1 originated from a non-
human primate virus.
STLV‑1 phylogeny
Since the first publication of a complete HTLV-1 provi-
ral genome [51], phylogenetic studies enabled to iden-
tify several HTLV-1 subtypes: Cosmopolitan subtype A,
which is found all over the world; subtypes B, D, E, F, G,
which are restricted to Central Africa; and Australo-Mel-
anesian subtype C which is the most divergent HTLV-1
subtype [8]. Based on molecular clock and phylogenetic
analyses, origin of HTLV-1 subtypes A, B, D, E was
inferred in a time frame of 27,300 ± 8200years , whereas
subtype F arose more than 10,000years ago.
In 1984, Watanabe et al. [52] demonstrated similari-
ties between restriction maps obtained using HTLV-1
from Robert Gallo’s laboratory or using Japanese simian
Adult T-cell Leukemia Virus (ATLV). ese results sug-
gested that HTLV-1 and simian ATLV shared a com-
mon ancestor. Other studies reported that HTLV-1 and
STLV-1 from Japanese monkeys, Red-faced monkeys,
Pig-tailed monkeys, AGM, Chimpanzees and baboons
(Papio cynocephalus) had the same genomic organization
i.e. LTR-gag-pol-env-pX-LTR [15, 20]. Sequence analyses
comparing Pig-tailed (Asian NHP) and AGM (African
NHP) STLV-1 sequences to HTLV-1 revealed 90% and
95% identity respectively. ese results suggested that
(1) STLV-1 could be separated into two subgroups: Asian
and African and that (2) HTLV-1 originated from the
African STLV-1 subgroup [16].
Phylogenetic studies revealed that HTLV-1 subtype B
is very closely related to STLV-1 strains infecting chim-
panzees (98% identity), Allen’s swamp monkeys (around
96% identity) and gorillas from Zaïre, Central African
Republic and Cameroon [45, 53–55]. STLV-1 strains
infecting Mandrillus sphinx, Cercopithecus cephus, C.
agilis, C. pogonias, G. agilis and C. nictitans share close
relationships with HTLV-1D and -F from Cameroon
and Gabon [49, 56–58]. Regarding HTLV-1 subtype E,

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Jégadoetal. Retrovirology (2019) 16:41
the Env region clusters with STLV-1 isolated from two
baboon species, Papio ursinus and Papio cynocephalus
[59]. No data has been so far reported about a simian
counterpart of HTLV-1G and HTLV-1A. Altogether,
the diversity of STLV-1 strains found in different NHPs
species and related to a given HTLV-1 subtype from the
same geographical areas is strongly supporting the con-
cept of multiple cross-species transmissions between
NHPs but also from NHPs to humans.
Most divergent STLV-1 strains were described in
Asian Macaca tonkeana (living in Indonesia) and
Macaca arctoides (living in India, ailand and China)
[60–62]. Macaca tonkeana virus is related to the most
divergent HTLV-1 subtype C that is present in Melane-
sia and Australia. Molecular clock data inferred STLV-1
introduction around 156,000 to 269,000years ago on
the Asian continent [59]. ese results suggest that
macaque infection with STLV-1 might have led to the
emergence of HTLV-1 in Asian human population.
Finally, Calvignac etal. [63] demonstrated that STLV-1
sequences could be amplified from bones samples origi-
nating from an early 20th century Chlorocebus pygeryth-
rus sample. erefore, it should now be possible to use
this technique to determine STLV-1 virus evolution over
time using available Egyptian or Asian NHP mummies.
STLV‑1 interspecies transmission
Prevalence of HTLV-1 may reach 1 to 40% in adults
depending on age, sex and geographic location [8]. It is
well known that HTLV-1 can be transmitted under dif-
ferent routes: sexual, mother-to-child and contact with
infected blood. However, STLV-1 transmission occurs
mostly through aggressive contacts instead of mother
to infant or sexual transmissions [64–68], even if sexual
transmission of STLV-1 is more important in NHPs such
as vervet [40].
Fig. 1 Epidemiology of Simian T-Leukemia Virus Type-1 in wild-caught or captive non-human primates (NHPs) from Asia and Africa. All studies
which reported STLV-1 infection in NHPs are listed. Orange and purple colors represent Asian and African STLV-1 infected NHPs, respectively.
Countries with both colors and hatching represent Asian and African NHPs hosted in geographical areas where they are not naturally present

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Jégadoetal. Retrovirology (2019) 16:41
STLV‑1 associated‑disease innaturally infected
animals
As it is the case for HTLV-1-infected individuals, most
STLV-1-infected monkeys remain lifelong asympto-
matic hosts [69]. For some unexplained reasons, TSP/
HAM cases have never been observed in infected
NHPs, even when those animals were living in animal
facilities for a long period. Phylogenetic studies per-
formed using samples from an African human TSP/
HAM patient showed that the viral sequence was highly
related to an STLV-1 sequence obtained from asympto-
matic West-African sooty mangabey [70]. Other strains
obtained from HTLV-1 African TSP/HAM patients also
clustered with STLV-1 strains obtained from asympto-
matic animals [71, 72]. It is well established that there is
no specific mutation in HTLV-1 genome that would be
associated with a given disease. Altogether, these data
suggest that the lack of TSP/HAM described cases in
NHPs might only be linked to the mode of viral trans-
mission rather than the age of infection.
On the contrary, a number of ATLL-like diseases
sharing clinical and pathological features with human
ATLL were reported in NHPs [24, 69, 73–79]. e first
report was made in STLV-1 infected macaques which
developed malignant lymphoma [80]. Subsequent stud-
ies reported similar symptoms in captive Papio anubis,
Gorillas and AGM [75–78, 81, 82]. In a recent study,
Tax-positive cells were detected in lymphoid and non-
lymphoid organs, mesenteric and axillary lymph nodes
and lung, but not in the blood from an infected Papio
anubis suffering from ATL [24]. In that case, skin lesion
biopsies also showed a massive dermal, hypodermic
and muscular cell infiltrates of positive CD3+ CD25+ T
cells, as described in human ATL.
Using STLV‑1 infected animals
After natural STLV‑1 infection
Given the high degree of sequence similarities between
STLV-1 and HTLV-1 genomes and the fact that both
viruses cause ATL, STLV-1 infected NHPs (Japanese
macaques, Mandrillus sphinx and Papio anubis) have
been used for performing molecular studies [79, 83–89]
(Table1). As HTLV-1, STLV-1 infection is mostly occur-
ring in CD4+ T-cells, although STLV-1 Tax expression
was also detected in bone marrow hematopoietic stem
cells invivo, and viral DNA was retrieved in all myeloid
and lymphoid cells derived from these infected progeni-
tors [86].
STLV-1 natural infection leads to Tax and SBZ (sim-
ian equivalent of HBZ) expression. Simian SBZ and Tax
amino-acid sequences are highly similar to human HBZ
and Tax (see Tables2 and 3). ese viral proteins also
Table 1 STLV‑1 naturally or experimentally infected non‑human primates (NHPs) described in published biological
studies
STLV-1 infection mechanisms, experimental treatments and immune response were analyzed in several NHP species
Studies Natural STLV‑1 infection STLV‑1 inter‑NHPs transmission Experimental
HTLV‑1 infection
Mechanisms of (co-)infection : retroviral
replication Miura et al. [79] Dube et al. [94] Kazanji et al. [96]
Ma et al. [83] Voevodin et al. [82] Kazanji et al. [97]
Castro et al. [84] Voevodin et al. [93] Kazanji et al. [98]
Termini et al. [85] Voevodin et al. [32] Mortreux et al. [99]
Furuta et al. [86] Voevodin et al. [53] Debacq et al. [100]
Drugs and vaccine treatments Yee et al. [87] McGinn et al. [95] Heraud et al. [101]
Souquière et al. [88] Pise-Masison et al. [102]
Souquière et al. [90] Valeri et al. [103]
Souquière et al. [111] McGinn et al. [104]
Sugata et al. [89]
Cytotoxic response Turpin et al. [24]
Afonso et al. [92]
Table 2 Amino acid sequence comparison ofHTLV‑1 HBZ
vs. STLV‑1 SBZ
ATK belongs to HTLV-1 A cosmopolitan subtype, EL to HTLV-1 B subtype, STLV-1
Papio anubis was obtained from an African NHP, while STLV-1 Mf5 was obtained
from an Asian NHP (Macaca fuscata)
HTLV‑1a ATK HTLV‑1b EL
HTLV-1a ATK – 74.27%
HTLV-1b EL 74.27% –
STLV-1 Papio anubis 83.01% 71.36%
STLV-1 Mf5 75.71% 61.43%

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Jégadoetal. Retrovirology (2019) 16:41
display activating properties on viral LTR and NF-κB
signaling pathways. As an example, a high STLV-1 pro-
viral load (PVL) is linked to IL-2, IL-6, IL-10, IFNγ and
TNF-α elevated expression in asymptomatic STLV-
1-infected Mandrillus sphinx [90]. Given well-estab-
lished results published in the HTLV-1 situation, this
is likely due to STLV-1 Tax expression, although this
hypothesis has not been formally demonstrated. IL-2
and IFNγ results were also obtained in asymptomatic
STLV-1-positive Macaca mulatta [87], while anti IFNγ
and TNF-α responses against Tax expressing cells were
also observed in STLV-1 infected baboons [85]. STLV-1
infection also promotes CTL response against STLV-1
Tax protein [84, 85].
Interestingly, TCF1 and LEF1, two T-cell specific pro-
teins, prevent Tax effect on viral LTR. eir expression
is high in thymocytes and thus counteract STLV-1 rep-
lication in thymus. On the opposite, their expression
and thus their effect is down-regulated in peripheral
blood T-cells (both in human and simian cells), thanks
to a Tax effect on STAT5a. is might explain why Tax
is more potent in these cells, and why HTLV-1 induces
ATL in the periphery [83].
Depending upon STLV-1 strain, SBZ protein
sequence is highly similar or contain insertions and
deletion compared to HBZ (see Table2). Nevertheless,
in both cases, animals can develop ATL [24, 79]. is
might be due to conservation of the N-terminal region
as well as of C-terminus basic leucin zipper domain
between human and simian viral proteins.
As its human counterpart, STLV-1 replication occurs
through clonal expansion of infected cells, both in
asymptomatic and ATL animals [24, 79]. Antiviral ther-
apy based on the use of azidothymidine (AZT) com-
bined with interferon-α (IFN-α) improves the survival
rate of ATL patients suffering from acute and chronic/
smoldering forms. A confirmation clinical trial using
these compounds was reported in an STLV-1 infected
Papio anubis suffering from ATL. e animal was
treated with a combination of AZT and interferon-α.
However, and contrary to human ATL, no clinical
improvement was observed. It would now be interest-
ing to determine post-mortem whether, this absence of
remission was linked to p53 mutation already present
when treatment started as shown in human ATL cases
who were not responding to AZT [91].
Given the fact that treating ATL patients is difficult,
and because an elevated PVL is a characteristic of ATL,
a study tested whether PVL decreases when valproate
and AZT were delivered to asymptomatic STLV-1-in-
fected animals [92]. is was indeed the case and it was
associated to an increased anti-Tax CTL response, thus
confirming the importance of immune response for con-
trolling viral infection [92]. In another study, STLV-1
infected asymptomatic Japanese monkey were inocu-
lated with mogamulizumab (anti-CCR4), a component
that is also used for human relapsed ATL cases. is led
to a strong reduction of STLV-1 proviral load [79, 89].
Altogether, these results support the fact that STLV-1
infected animals represent a useful tool for testing drugs.
Finally, a recent study was performed in two asympto-
matic STLV-1-infected animals. is showed that immu-
nization using recombinant vaccinia viruses expressing
either Tax-22 (which cannot activate the NF-kB pathway)
or an HBZ LL/AA mutant (which is partially impaired for
blocking Tax ability to induce transcription) was linked
to a temporary decrease of STLV-1 PVL [89].
After STLV‑1 interspecies transmission
A limited number of reports described STLV-1 inter-sim-
ian species transmission [32, 53, 93, 94] (Table1). In one
report and following an unknown mode of transmission,
it was shown that baboons accidentally infected with a
rhesus macaque STLV-1 virus, developed leukemia/lym-
phoma at a high frequency [93]. is is the only reported
case suggesting that inter-simian species transmission
might impact viral pathogenesis. Experimental infection
of pig-tailed macaques with sooty mangabey STLV-1 was
also tested. Animals maintained low antibody titers and
displayed a high mortality rate without any identified
cause [95]. Finally, another work reported tantalus and
patas animals artificially infected with STLV-1 from other
species. All animals became infected, as shown by PCR
results, even if one stayed seronegative due to mutations
in the genome [94]. Why were these pol mutant viruses
still able to infect animals remains unexplained.
After articial HTLV‑1 infection
Finally, given the high degree of similarity between
HTLV-1 and STLV-1 genomes and the abundance of
molecular tools available in the HTLV-1 field, some labo-
ratories decided to use the HTLV-1 molecular clone or
HTLV-1 infected cells to perform studies in non-human
primates (Table 1). Artificial infection after inoculation
Table 3 Amino acid sequence comparison of HTLV‑1 Tax
vs. STLV‑1 Tax
ATK belongs to HTLV-1 A cosmopolitan subtype, EL to HTLV-1 B subtype, STLV-1
Papio anubis was obtained from an African NHP, while STLV-1 Mf5 was obtained
from an Asian NHP (Macaca fuscata)
HTLV‑1a ATK HTLV‑1b EL
HTLV-1a ATK – 97.26%
HTLV-1b EL 97.26% –
STLV-1 Papio anubis 96.03% 95.74%
STLV-1 Mf5 92.92% 93.31%

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Jégadoetal. Retrovirology (2019) 16:41
of HTLV-1 to primates provides an inestimable tool to
study primo-infection and viral dissemination, invivo, a
process that is inaccessible in humans. HTLV-1 infection
of Saimiri sciureus, i.e. non-human primates that are not
naturally infected with STLV-1 [96], demonstrated that
lymphoid organs represent the major viral reservoir [97].
As in HTLV-1 infected humans and STLV-1 naturally-
infected animals, IL-2, IL-10, IFNγ levels also increased
after HTLV-1 infection [98]. In Saimiri sciureus, the
virus also replicates through clonal expansion after hav-
ing used reverse transcription (RT) at the initial stages
[99] and it causes ATL [100]. As in baboons treated with
AZT/IFN [24], arsenic combined to IFN-α was not able
to lead to HTLV-1 proviral load reduction, even if the
number of circulating ATL flower cells decreased for
some unexplained reason [101].
Studies were also performed in pig-tailed and rhesus
macaques inoculated with autologous cells previously
transfected with the HTLV-1 ACH molecular clone
[102–104]. Following infection with wild-type HTLV-
1, pig-tailed macaques developed a series of extremely
aggressive diseases that were different from ATL. ese
results therefore suggest that this animal model can-
not be used for studying events that are resulting from
HTLV-1 infection.
Consequences of rhesus macaque infection with the
same molecular clone were different since animals
remained asymptomatic. HTLV-1 p12 and p8 proteins
have been shown previously to increase NFAT activity,
IL-2 production and STAT-5 activity, while p30 controls
viral expression at the post-transcriptional level invitro
(for a review, see [105, 106]). us, this simian model was
useful to investigate the role of p12, p13, and p30 auxil-
iary proteins in vivo [102, 103]. is allowed research-
ers to show that p12 and p30 are required for allowing
HTLV-1 presence and replication in dendritic cells [103],
while p12 and p8 are necessary for allowing a viral resist-
ance to CTL responses. ese studies provided the first
invivo evidence on the mechanisms that HTLV-1 uses
to establish chronic infection and on the crucial role of
myeloid cells in that process.
Interestingly, the authors also demonstrated that the
results obtained in rhesus macaques were different from
those obtained in rabbits infected with the same viral
clones, thus reinforcing the fact that NHPs are the more
relevant system for studying HTLV-1 pathogenesis.
PTLV retroviral coinfection inNHPs andinhumans
In addition to STLV-1, other retroviruses, i.e. Simian
Immunodeficiency Virus (SIV) and Simian Foamy Virus
(SFV) infect NHPs. Cases of natural coinfection have
been reported both in humans and in NHPs: HTLV-1/
HIV-1, HTLV-1/HFV, STLV-1/SFV or STLV-1/SIV-1
[67, 107–115]. HIV-1/HTLV-1 coinfection leads to sig-
nificant increase of HTLV-1 PVL as well as on a possible
delay in HIV-1 pathogenesis in humans [107, 108, 116].
Anti-HIV-1 therapy promotes an increase in HTLV-1
PVL in HIV-1/HTLV-1 coinfected carriers. ese
results strongly suggest that both retroviruses compete
for CD4+ T-cell infection. However, it is worth not-
ing that opposite results were obtained in other studies
[117–121].
Natural STLV-1/SIV-1 co-infection induces the devel-
opment of a neoplastic disease in sooty mangabey [122]
and of a lymphoproliferative disease in AGM [123].
Souquière et al. described pathological manifestations,
i.e. infective dermatitis and scabies, in two STLV-1/SIV-1
co-infected mandrills [111], while no clinical sign has
been reported previously in STLV-1 naturally infected
mandrills [90]. us, these symptoms could be due to
co-infection. Ongoing experiments should allow us to
determine whether STLV-1 clonal expansion impacts SIV
replication invivo.
Finally, blood SFV proviral load from STLV-1/SFV nat-
urally co-infected Papio anubis, was recently shown to be
much higher compared to SFV mono-infected animals
[124]. ese results either suggest that cells might be co-
infected with both retroviruses, with STLV-1 promoting
clonal expansion, or that soluble STLV-1 Tax transactiva-
tor enters SFV-infected cells where it promotes viral rep-
lication. Ongoing experiments should allow us to answer
this question.
Altogether, these data demonstrate that STLV-1 is a
useful tool to understand mechanisms of HTLV-1 trans-
mission and ATL pathogenesis. PTLV-1 mono-infected
as well as SIV co-infected animals could also be used to
develop possible new anti-HTLV-1 clinical approaches
and to modify anti-HIV treatment.
Acknowledgements
BJ is supported by Labex Ecofect, RM is supported by Ecole Normale Supé-
rieure de Lyon. RM is part of the French Laboratory of Excellence project
ECOFECT (ANR-11-LABX-0048). The authors acknowledge the support Fonda-
tion pour la recherche médicale (équipe Labellisée). The authors thank Dr C.
Journo for her helpful comments.
Authors’ contributions
BJ, HD, FK and RM wrote the manuscript. All authors read and approved the
final manuscript.
Funding
RM is part of the French Laboratory of Excellence project ECOFECT (ANR-
11-LABX-0048). The authors acknowledge the support Fondation pour la
recherche médicale (équipe Labellisée DEQ20180339200). BJ is supported by
Labex Ecofect, RM is supported by Ecole Normale Supérieure de Lyon. HD is
funded by INSERM.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.

Page 7 of 10
Jégadoetal. Retrovirology (2019) 16:41
Consent for publication
Not applicable.
Competing interests
Not applicable.
Author details
1 International Center for Research in Infectiology, Retroviral Oncogen-
esis Laboratory, INSERM U1111 - Université Claude Bernard Lyon 1, CNRS,
UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Fondation pour
la Recherche Médicale, Labex Ecofect, Lyon, France. 2 Laboratory of Molecular
Virology, George Mason University, Manassas, VA, USA.
Received: 24 July 2019 Accepted: 7 December 2019
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