HTLV-1: a Real Pathogen Or a Runaway Guest of a Diseased Cell?

Home , Alpharetrovirus, Deltaretrovirus, Epsilonretrovirus

J Biosci Vol. 43, No. 4, September 2018, pp. 785–795 Ó Indian Academy of Sciences DOI: 10.1007/s12038-018-9787-9 Review

HTLV-1: A real pathogen or a runaway guest of a diseased cell?

LIBKANZAKI Laboratory of Bioprospection, Department of Pharmacy, University of Brasilia, Brası´lia, DF CEP 70.910-900, Brazil

(Email, [email protected]) MS received 9 October 2017; accepted 31 May 2018; published online 4 August 2018

The human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus claimed to be aetiologically linked to the adult T-cell leukaemia/lymphoma (ATLL) and associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other minor pathologies. HTLV-1 infection is worldwide distributed, despite its heterogeneous prevalence. Environmental factors and host-genetic background are very likely to determine the epidemiological proﬁle of HTLV-1 prevalence and related disease conﬁnement in distinct human ethnic populations and geographical coordinates, which raises the question if the virus is a real pathogen or a runaway well-organized packed genome of a burden host cell near death process. New methodological approaches need to be proposed and applied in order to prove or discard the hypotheses emerged in the present review.

Keywords. Deltaretrovirus; environment; HTLV; ionizing radiation

1. Introduction lymphoma (mycosis fungoides) (Poiesz et al. 1980; Gallo 2005). Previously, in 1977, Takatsuki and coworkers, in The factors that determine the incidence and prevalence of Kyoto, Japan, described a new haematological disease, the certain infectious diseases seem to be well established, such adult T-cell leukaemia (ATL) that later on was aetiologically as the host-genetic background with special focus on the linked to human T-cell lymphotropic virus (HTLV) (Takat- major histocompatibility complex and the innate immunity. suki 2005). After reviewing the patient records from whom But also, climate conditions and environmental contamina- HTLV was first isolated, it was concluded to be also ATL. In tion associated with geographical coordinates and geological 1998, the International Committee on Taxonomy of Virus profiles have a profound effect on both host health and established the seven genera (Alpharetrovirus, Betaretro- parasite success in the established relationship. Infectious virus, Deltaretrovirus, Epsilonretrovirus, Gammaretrovirus, diseases are particularly distinct, as the interactions between Lentivirus and Spumavirus) of the retroviridae family, the pathogen and the host immune system play a crucial role including the Deltaretrovirus genus enclosing the HTLV in the outcome of host health and parasite survival and species (http://www.ictvonline.org/taxonomyReleases.asp). evolution. The pathogen and host interrelationship, mainly administered by the immune system, is not solely circum- scribed by these players, but also influenced by a plethora of 2. The Deltaretrovirus genus factors, with extraordinary emphasis on the environment settings, including toxic metal content of foods, mainly of The Deltaretrovirus genus comprises the HTLV types 1, 2, 3 botanical origin and meat of animals (Anche et al. 2015; and 4 (HTLV-1/2/3/4), the simian T-cell lymphotropic virus Bickler et al. 2016; de la Penã-Lo´pez and Remolina-Bonilla types 1, 2, 3 and 4 (STLV-1/2/3/4) and the bovine leukaemia 2016; Pitchappan 2016; Sochorova´ et al. 2016; Maria John virus (BLV) (Gessain et al. 2013; Lairmore 2014; LeBreton et al. 2017; Padayachee et al. 2017). et al. 2014). Among the human deltaretroviruses, only The first human retrovirus was isolated and characterized HTLV-1 has been aetiologically linked to human diseases as in Gallo’s laboratory in 1979, in Bethesda, MD, USA ATL/lymphoma (ATLL) and the tropical spastic paraparesis (Coffin 2015). Initially, the virus was named human cuta- (TSP), also known in Japan as HTLV-1-associated neous T-cell lymphoma virus, strain CR, HTLVcr, referring myelopathy (HAM), besides other pathologies related to the to the patient’s name (CR) diagnosed with a cutaneous T-cell abnormal lymphocytic proliferation induced by the http://www.ias.ac.in/jbiosci 785 786 LIB Kanzaki interaction of viral proteins with the host cell biochemical The retrovirus long-terminal repeat, LTR, controls virus machinery. The other members of the HTLV group were not expression through their cis acting elements, U3, R and U5. yet aetiologically linked to any disease, their role in human The HTLV-1 accessory proteins, p30, p12 and p13, play pathologies is not clear, even though some researchers claim auxiliary roles in viral oncogenesis as latency also. The that HTLV-2 would also be a causative agent of neurological HTLV-1 infected subjects could behave just as virus carriers disorders (Biglione et al. 2003; Montanheiro et al. 2008; without any visible pathological abnormality and symp- Biswas et al. 2009). The HTLV types 3 and 4 were also not tomless, or present any related disease in progression which, related to any disease, and solely found among indigenous in both cases, represent a fine and delicate intrinsic virus– people in Central Africa (LeBreton et al. 2014). host cellular and molecular orchestration that still needs Closely related to the human deltaretroviruses, the STLV- more insights to completely understand, unravelling the role 1/2/3/4 were transmitted to humans by non-human primates, played by the cellular and viral gene products (Boxus and very probably in Africa, in an apparently long-term adap- Willems 2009). tation. Altogether, HTLVs and STLVs compose of the group of the primate T-lymphotropic viruses (PTLVs) due to their intimate phylogenetic relationship (Slattery et al. 1999; 4. Human Deltaretrovirus and the host immune system Filippone et al. 2015; Richard et al. 2016). Inferred from molecular analysis with paleobiogeographical and ecological T as well as B lymphocytes and dendritic cells are the main data, Reid et al.(2016) concluded that it was very likely that targets of deltaretroviruses, even though monocytes and STLV-1 transmission from a macaque (Macaca sp.) to an macrophages are also susceptible to HTLV-1 infection. The orangutan (Pongo sp.) occurred around 207.5–17.2 kya (late cell receptor for the virion envelope (ENV) glycoprotein, the Pleistocene) and to humans between 125.9 and 10.4 kya. glucose transporter type 1 (GLUT1), mediates the host cell Recently, two individuals in Gabon, Central Africa, were membrane fusion to the virion surface and transmembrane found to be infected by HTLV-4/STLV-4 after being bitten ENV glycoproteins and therefore infection, assisted by other by a gorilla, as both deltaretrovirus, from human and gorilla, cellular factors as the heparan sulphate proteoglycans showed more than 99.4% nucleotide identity. The geo- (HSPG) and the vascular endothelial growth factor (VEGF)- graphical origin of the PTLV group is still on debate, but 165 receptor neuropilin 1 (NRP-1) (Jones et al. 2011; confined to the limits of Africa and Asia among their non- Kannian et al. 2013; Maeda et al. 2015). human primate hosts (Slattery et al. 1999; LeBreton et al. HTLV-1 preferentially presents tropism for CD4? T-cells, 2014; Filippone et al. 2015; Reid et al. 2016; Richard et al. so the highest proviral load is detected among these cells, 2016). and in much less amount in CD8? T-cells, therefore ATL cells are mainly represented by CD4? T-cells. On the other hand, HTLV-2 mainly infects CD8? T-cells (Bangham et al. 3. Deltaretrovirus genome composition and disease 2014; Maeda et al. 2015). Scarce information is available for implications HTLV-3 and 4, as studies are still restricted to the genome of these viruses, as few subjects were found to be infected by Retroviral genomes are organized in the 50-LTR-gag-pro- them in Central Africa. Apparently, both viruses share the pol-env-LTR-30 structure, enclosing sequences that code for same host cell receptors as HTLV-1 and 2 (Gessain et al. proteins that build-up the virion architecture (gag and pol 2013; Mahieux and Gessain 2013). Infection of monocytes genes), and enzymes necessary for molecular plasticity in the by HTLV-1 is likely a prerequisite for viral persistence in virus assembly (pro and pol genes). Also, regulatory/acces- humans, as also the viral load would determine the disease sory factors are coded by the retroviral genome, in attempts onset and progression (Bellon and Nicot 2015; de Castro- to circumvent the host immune response through controlling Amarante et al. 2015; Hyun et al. 2015). gene function and host virus interaction, usually deleterious In vitro studies have demonstrated that the HTLV-1 Tax for the host (Skalka 2014). oncoprotein interacts with the Toll-dependent TIR-domain- The HTLV-1 9 kb genome, besides the classical organi- containing adapter-inducing interferon-b (TRIF), which zation of all retroviruses, possesses gene sequence coding suppresses the innate immune response (Mahieux and Ges- for the regulatory proteins Tax, Rex and HTLV-1 bZIP factor sain 2011). Both Tax and HBZ expressions induce, through (HBZ). The Tax and HBZ proteins, coded in the plus and multiple pathways, telomerase activity in HTLV-1 infected minus strands, respectively, in the pX region, play a major cells, preventing them to enter a senescence state (Bellon role in viral pathogenesis, HTLV-1-associated inflammatory and Nicot 2015), but the infected cells concomitantly diseases and ATLL. Despite this, in some pathways, Tax and expressing Tax and the cell adhesion molecule 1 (CADM1/ HBZ act antagonically, as the Tax protein is important for TSLC1) are efficiently eliminated by TCD8? cytotoxic cells, the initiation of viral oncogenesis but HBZ balances Tax during MHC presentation (Manivannan et al. 2016). activity, maintaining the neoplastic state (Philip et al. 2014). Therefore in someway, HBZ and Tax play complementary, HTLV-1 escape 787 opposite and replacing roles during the fate of infected cells, highest prevalence of HTLV-1 infection in the world has deciding the asymptomatic or disease state of HTLV-1 car- been recently found among indigenous Australians (Ein- rier hosts. Expressed HBZ peptides compromise the host siedel et al. 2016). immunity, counteracting NF-jB activation by Tax, therefore Phylogenetic studies trace back the origin of HTLV-1 to inhibiting senescence of the infected cells, which promote central Africa and virus dissemination through human full phenotype exposition of a neoplastic state, aggressively migration during commercial trips of Portuguese ships from bombarding the host organism with cytokine and chemokine Africa to Japan, and also by slave trade from Africa to the signalling in cell response to HTLV peptide presentation, American continent during the 16th to the 19th century leading to inflammation and consequent malignant trans- period (Gessain et al. 1992; Carpentier et al. 2015). Also, formation. Anyway, Human Leucocyte Antigen (HLA) these studies show a close genetic proximity between HTLV- adapted to HBZ peptides have demonstrated a protective role 1 and STLV-1, very probably indicating that human ances- for the host, diminishing the HTLV-1 proviral load, as their trals in Africa acquired the virus from nonhuman primates, presentation to T-cytotoxic cells eliminate HTLV-1 infected and events of human migration and geographical isolation in cells (Macnamara et al. 2010; Rowan et al. 2014; Mani- different chronological settings, favoured the generation of vannan et al. 2016). The cytokine cargo generates besides distinct human genetic background accompanied by HTLV-1 inflammation, consequent neuronal demyelination in HAM genetic variability, ultimately within seven subtype strains, patients. Pinto et al.(2015) found that CD4? T-cell activa- from A to G, as the Central African subtypes B, D, E, F and tion was related to elevated CD3e, LCK, ZAP70 and VAV1 G, the Australo-Melanesian subtype C and the Cosmopolitan gene expression in HAM/TSP patients compared to subtype A (Gessain et al. 1992; Carpentier et al. 2015). asymptomatic HTLV-1 carriers, as also Medina et al.(2016) Currently, pockets of high HTLV-1 prevalence have been detected higher levels of Tax protein in the plasma of HAM/ identified globally, usually found in descendants of African TSP patients than among HTLV-1 asymptomatic carriers, as and Japanese populations (Brucato et al. 2010; Gessain and the infected cells of asymptomatic carriers could ubiquitinate Cassar 2012). In Brazil, the highest prevalence of HTLV-1 the Tax protein, directing them to proteasomal degradation. infection was recorded in the northeast region, mainly in Besides, Araya et al.(2014) showed that Tax represses the Bahia, Maranhaõ and Para´ states (Carneiro-Proietti et al. transcription factor FOXP3 in Tregs cells, which ultimately 2002; Catalan-Soares et al. 2005; Brucato et al. 2010; stimulate interferon (IFN)-c production and consequently Guimara˜es de Souza et al. 2012; Pessoâ et al. 2014; Viana promote inflammation, supporting the hypothesis by these et al. 2014), where African descendants predominate in the authors that Th1-like cells (Tregs cells) exert a central role in overall population. According to epidemiological studies, it the pathogenesis of neuromyelopathies, while in blood cir- is estimated that 10–20 million people are infected by culation, the cytokine cargo cooperates with T lymphocyte HTLV-1 globally. Nowadays, it seems that Brazil reveals the phenotype transformation into a malignant state, the ATLL. highest endemic area for the virus according to Carneiro- In both cases, HBZ plays a pivotal role after Tax silencing Proietti et al.(2002) with the highest absolute number of (Giam and Semmes 2016; Yasuma et al. 2016). HTLV-1 infected subjects (Catalan-Soares et al. 2005; Gui- mara˜es de Souza et al. 2012).

5. HTLV types 1 and 2 prevalence 6. Discussion The deltaretrovirus infected leucocytes are transmitted through sexual intercourse, more effectively from man to Despite the heterogeneous prevalence of HTLV-1 infection woman; and during breast feeding of infected mothers to everywhere, globalized human movement is of crucial their lactating babies. As the deltaretrovirions are tightly importance in the dynamics of HTLV-1 epidemiology. The associated with the host cell, HTLV transmission and virus containment in familiar nuclei reinforced by geo- infection is more prevalent in familiar nuclei (Percher et al. graphical barriers has been changed. The deltaretrovirus 2016). biological behaviour would explain the low rate of trans- Since the initial isolation and characterization of HTLV-1 mission, as the virion is intimately associated with the cell in the United States and the establishment of the aetiological membrane and its spread from one cell to another is medi- link to the ATLL in Japan, and to myelopathy in South ated by viral synapses as also by extracellular-rich carbo- America, Caribbean Islands and Japan, epidemiological hydrate structures attached to the cell membrane (Igakura studies pointed out to a dense prevalence of the virus in et al. 2003; Pais-Correia et al. 2010). Also, virus latency Japan, Caribbean Islands, Central Africa and in Solomon after genome integration would prevent transmission, as the Islands in the Pacific Sea near Australia (Gessain and Cassar probability of an infected cell to carry the virus to another 2012; O’Brien et al. 2013; Araujo et al. 2014; Chang et al. host is reduced, given that if the virus is actively replicating, 2014) and more recently, in Iran (Salehi et al. 2016). The which means a direct proportional rate between more 788 LIB Kanzaki infected cells and high-viral load (Sobata et al. 2015). authors claimed that the virus was not the leukaemogenic Besides, repeated episodes of virus exposure to the host agent (Lieberman et al. 1992). A comparison between would be necessary for virus transmission, independently if HTLV-1 and MLV shows that both viruses were classified as it happens by sexual intercourse, breast feeding or another type C retroviruses, just visualized when budding from the route. Therefore, HTLV-1 familiar transmission is more cell membrane; moreover, the Env protein of both viruses is prone to occur, due to the frequent host exposure to the virus very close structurally, as also they are ecotropic and HTLV- (da Costa et al. 2013; Percher et al. 2016). In a previous 1 rarely causes disease as it happens to MLV (Kim et al. study, in a highly inbred population, in a village in the 2003, 2004). Besides the above arguments, we found four central Marajo´ island, in Brazil, an elevated HTLV-1 out of 131 (3.05%) uterine cervix cancer patients to be prevalence was detected, emphasizing the familiar clusters HTLV-1 positive by the ELISA/WB assay and confirmed by of HTLV-1 infection, nevertheless without any public health PCR amplification of ltr, gag and tax sequences. Also three control, 15 years later, the HTLV-1 prevalence remained healthcare workers had the same results as the uterine cervix unchanged (Pamplona et al. 2010; Kanzaki 2015). cancer patients. The cancer patients and the healthcare Viral replication plays a major role defining the chance of workers had common events of ionizing irradiation expo- HTLV transmission, and among the factors that would pre- sure, as cancer patients were treated with cobalt therapy and dispose to this condition, the stress exerts an important three healthcare workers manipulated the irradiation appa- function, mainly considering the way of living in our mod- ratus or utilized cobalt-60 pellets (Kanzaki 1995; Kanzaki ern civilization. It has been reported the association between et al. 1997). psychological stress and immediate immunomodulation, The frequency of WB indeterminates is a common finding experimentally characterized by the response of transcrip- in HTLV-1 serological screening (Kanzaki et al. 1997; tional and cell population profile of peripheral blood leu- Abrams et al. 2011; Umeki et al. 2017). In order to state that cocytes to endocrine and autonomic factors (Breen et al. someone carries HTLV type 1 or 2, the subject’s serum must 2015), therefore, hypothetically there is a correlation have antibodies against at least one of the Gag peptides and between HTLV-1-related disease prevalence and human one of the Env peptides. If someone has antibodies exclu- population density, as it is observed for example in large sively against the Gag peptides, or the Env peptides, it will metropolis in Japan. be classified as WB indeterminate (Miller 2016). Filippone It is not well understood how environmental factors would et al.(2012) found what would be some pattern of the HTLV contribute to HTLV-1 infection and prevalence, but in a WB indeterminate profile in some native populations in previous review (Barros Kanzaki 2006), based on data South Cameron, Africa. Some reports raise the possibility obtained among cancer patients and geographic areas of that HTLV WB indeterminate represents cross-reaction to abnormal exposure to radiation, it was proposed that ioniz- peptides coded by the HTLV-1-related endogenous retroviral ing radiation would trigger the provirus gene transcription sequences, HRES (Perl et al. 1989; Banki et al. 1992; Per- and viral replication or either. Now, it could also be zova et al. 2015). Perl et al.(1989) presumed that HRES emphasized the hypothesis concerning the reorganization endogenized early, during the developmental period, in the and/or recombination of endogenous retroviral gene seg- primate genome. The most homologous nucleotide regions ments, when exposed to ionizing radiation, to generate the of HRES to HTLV-1 and HTLV-2 were in the open reading deltaretrovirus genome and virions. Despite previous work frames (ORFs) that code for p25 and/or p15, as also in the ltr by Furth and Furth (1936), on the induction of neoplastic region. In addition, there were homologous peptides coded diseases in mice by X-ray irradiation, the above proposed in the gag region of the human immunodeficiency virus type hypothesis, based on another model, was partially discussed 2 (HIV-2) and the feline sarcoma virus (FSV) (Perl et al. earlier in 1952, as Kaplan and Brown reported the results of 1989). Very recently, Farkasˇova´ et al.(2017) described what experiments dealing with the induction of lymphoid tumour they proposed to be, the first endogenous deltaretrovirus, development in mice by ionizing radiation (Kaplan and MINERVa, found in the germline of long-fingered bats Brown 1952) and, sustained on assays conducted by Gross (Miniopterus natalensis), in which the endogenization per- in 1958, after the detection and characterization of leukae- iod was estimated to have occurred 20–45 million years ago. mogenic retroviruses in irradiated mice developing lym- The predicted Gag proteins, constituent of the matrix and phoblastic leukaemia (Gross 1958), Lieberman and Kaplan capsid, exhibited 30.8% and 45.4% identity, respectively, to (1959) found that X-ray irradiation induced the expression of HTLV-1 correspondent proteins. Also, regulatory genes as an endogenous ecotropic virus, the murine leukaemia virus tax and rex were detected, in contrast to the sequence coding (MLV), a type C retrovirus (endogenous gammaretrovirus), for the nucleocapsid (NC), protease (PR), polymerase (POL) also known as the radiation leukaemia virus, that lately was and ENV proteins that were deleted. Therefore, taking into established to act as the aetiologic agent of leukaemia/lym- account all the aforementioned reports, the model of radia- phoma, isolated from thymic lymphoma of X-ray irradiated tion leukaemia virus activation, in the context here dis- C57BL/Ka mice (Haas et al. 1987), even though some cussed, could be the initial steps to understand the possible HTLV-1 escape 789 origin of HTLV-1 in their hosts, also considering the exis- 2008; Agoni et al. 2013; Perzova et al. 2015; Farkasˇova tence of endogenous retroviruses related to the genera et al. 2017). deltaretrovirus, lentivirus and gammaretrovirus, as the HRES Curiously, in the Middle East, in the Islamic Republic of and MINERVa. As literally stated by Cloyd (1996), ‘En- Iran, the HTLV-1 prevalence is high, so that in some areas it dogenous retroviruses in animals and humans probably reaches 3%. It is well-known that the involvement of the evolved from transposable elements, some of them gaining Iranian population in uranium mining facilities to fuel local the ability to package themselves in a virion structure, to nuclear power reactors (Mahzounieh et al. 2015; Uddin et al. leave the cell and infect another cell’, therefore as expected, 2015; Salehi et al. 2016). Despite the fact that there is no the endogenous retrovirus becomes exogenous when it report associated with HTLV-1 prevalence or disease-related leaves the cell and infects another cell. That is another conditions among atomic bomb survivors in Japan (Matsuo argument that sums up to the previously mentioned. et al. 1995), the direct radioactivity doses were extremely In addition, the rearrangement of nucleotide sequences in high (Tonda et al. 2012), such that the effects were catas- the genome of any vertebrate is well illustrated by the trophic with immediate high mortality similarly in propor- generation of immunoglobulin and T-cell receptor diversity tion to Chernobyl radioactivity accident. Natural exposure to (Flajnik 2014). Murray (2015) discussed the role played by radioactivity or even in patients submitted to radiotherapy is the Tigger transposon in the inactivation of an intact/ much less aggressive than radioactivity exposure in Japan or ancestral A-23 HLA allele. Therefore, it is the widespread Chernobyl (Cardis et al. 1996; Beresford et al. 2016). and fundamental evolutionary function of transposons in the Preston et al.(1994) found that among atomic bomb existence, survival and evolution of any living organism. survivors in Japan, followed up from 1950 to 1987, there Evsikov and Marıń de Evsikova (2016) advocated that was a high risk for developing all subtypes of leukaemia transposable elements connect genetic and epigenetic ele- except for ATLL. Matsuo et al.(1995) analysed the effects ments that could generate genomic instability in somatic of radiation among atomic bomb survivors in the cities of cells, leading or not to successful development. Epigenetics Nagasaki and Hiroshima concerning the rate of HTLV-1 are conceptually dealing with the phenotypic variation infection and the incidence of ATLL, and concluded that originated from the interplay between the developmental and there were no significant relationship between the events. environmental factors which ultimately control gene tran- Nagasaki has a higher rate of HTLV-1 infection than Hir- scription at all cellular levels, driving to evolutionary pres- oshima, as 6.36% and 0.79% of HTLV-1 seroprevalence, sure, revealing genome adaptation to the environment. respectively. However, there is no report of HTLV-1 sero- It has been reported that exposure to ionizing radiation prevalence and disease-related incidence before 1945 in elevates the incidence of diseases linked to deltaretrovirus Japan as the virus was recognized in 1980 and ATLL was infection, likely among cattle infected with the BLV, in the described in 1977 (Poiesz et al. 1980; Takatsuki 2005). Soviet Republic (Ponomareva 2008). In the Brazilian state of Ohishi et al.(1996) carried out immunological assays to Bahia, where it is located one of the largest uranium deposit investigate the possible association of HTLV-1 infected in the country (Tagliaferro et al. 1999), it was also found to atomic bomb survivors in Nagasaki with autoimmune dis- be the area with the highest prevalence of HTLV-1 in Brazil order prevalence, and could not find any relationship sta- (Magalha˜es et al. 2008; Mello et al. 2014; Nunes et al. tistically significant but found an increased level of 2015). Radon gas derived from the decay of radium-226, immunoglobulin M (IgM) among HTLV-1 seropositive naturally produced in places of uranium mining facilities, survivors. Nothing was reported about any association has been aetiologically associated with lung cancer, as a between radiation exposure and HTLV-1 prevalence. Ari- direct action to the airway cells. Experimental studies in cell sawa et al.(1998) also conducted epidemiological studies on culture have shown that a particle radiation, in the form of HTLV-1 infection among atomic bomb survivors in Naga- energy released by randon gas and decay progeny, induces saki, but did not mention any link between the rates of cell genomic instability, which eventually would activate HTLV-1 infection and exposure to radiation, even though deltaretrovirus gene sequences from the latent state in the they concluded about the influence of HTLV-1 infection on host DNA (Lino Ada et al. 2015; Sumption et al. 2015; Leng mortality considering co-infection by hepatitis C virus and et al. 2016). Therefore, at least two factors could be asso- hepatitis B virus other than the ATLL. Arisawa et al.(2006) ciated with the elevated prevalence of HTLV-1 among performed a longitudinal study with 2729 HTLV-1 infected human subjects in Bahia: the afrodescendency of the popu- atomic bomb survivors in Nagasaki Prefecture in order to lation and the exposure to ionizing radiation. In such con- evaluate the incidence of cancer during 15.4 years and did ditions, hypothetically, carriers of HRES/MINERVa and/or not find any significant increment in cancer incidence except HTLV-1 genome when exposed to ionizing radiation would for ATLL, further from the other reports, there is no infor- have transcriptionally activated retroviral genes and would mation regarding the association between HTLV-1 preva- have more probability to transmit the virus, as previously lence and exposure to radiation. Hida et al.(2010) reported discussed (Perl et al. 1989; Banki et al. 1992; Arruda et al. the association between HTLV-1 infection and the incidence 790 LIB Kanzaki of Sjo¨gren syndrome among atomic bomb survivors in (RNS) which causes oxidative damage and tissue dysfunc- Nagasaki, but could not find any association between radi- tion, besides the participation or interference in the natural ation exposure and HTLV-1 infection prevalence as also the flow of signalling molecules in the biochemical mechanisms association with the incidence of Sjo¨gren syndrome. of the proteasome, endoplasmic reticulum and mitochondria Based on the aforementioned data, it is difficult to reach (proterome) (Di Meo et al. 2016). These complex, coupled any conclusion related to possible association between ion- and interacting organelles, the proterome, mainly signalled izing radiation and HTLV-1 genesis or activation from its by ROS and RNS, plays a dynamic and dual role, that could proviral form. Any research work comparing HTLV-1 sero- be noxious or beneficial for the living system, but ultimately prevalence before August 1945 and after the atomic bomb prevent through regulatory mechanisms, autophagy and detonation in Nagasaki and Hiroshima is not known so far. apoptosis (Di Meo et al. 2016; Chirumbolo and Bjørklund Retrospective studies reclassified acute leukaemia in order to 2017). The stressors, xenobiotics and derived compounds of fit the diagnosis as ATLL, therefore it is quite impossible to plants and microorganisms, interfere with the mechanism of draw any accurate conclusion, besides the amount of energy protein cleavage by immunoproteasome, exemplifying viral released was instantaneously massive and harmful, enough to proteins, concomitantly with the inability of the endoplasmic induce a large array of chromosomal instability and muta- reticulum to synthesize the histocompatibility proteins, tions. Viral evolution is a dynamic process and highly would hamper the presentation of viral antigens to effector ordered, mutations are accepted or denied and certainly an cells of the immune system, which would allow the virus to excess of genomic chaotic changes is dismissed, therefore escape immune surveillance. In this way, ROS and RNS under these perspectives, a long period of time would be production would interfere with the proterome in the basic expected to analyse the genome of deltaretroviruses in the mechanisms of viral protein processing and selection for the atomic bomb survivors and their descendants in Japan, con- major histocompatibility antigen presentation to the immune sidering the levels of ionizing radiation exposure. cells (Osna et al. 2012; Chirumbolo and Bjørklund 2017). Ecologically considering the relationship between the host Besides the interference of ROS and RNS in response to the and virus, HTLV-1 infection and the host health status rep- adaptive immune response against infection, the innate resents a challenging model of an odd relationship, as just immunity is also affected, as the mitochondrial ROS about 5–10% of infected subjects develop ATLL, TSP/HAM (mROS) production, mitochondrial DNA release and mito- or other related diseases, which depends least on the host chondrial antivirus signalling protein (MAVS) fundamen- geographic inhabiting area encompassing exposure to the tally ignite the innate immune response against viral environment and the genetic background (Gessain and infection and other aggressions to the cell; mROS produc- Cassar 2012; McGill et al. 2012). As previously debated, tion regulates the expression of the nucleotide-binding environmental factors should play an important role in domain leucine-rich repeat-containing receptors such as infection and disease. In addition to ionizing radiation, a NLRP3, which is directly involved in the inflammasome common issue that concerns is environmental contamination activation (Sandhir et al. 2017), so as a consequence, the of water and food. Analyses of milk samples from lactating mitochondrial homeostasis, that is essential for the innate mothers in different countries have shown significant con- immune response activation, will be disturbed and the cell tents of heavy metals and sometimes mycotoxins (Cunha becomes more vulnerable to retrovirus activation, or more et al. 2013; Marques et al. 2013; Castro et al. 2014; Chao active to eliminate virus infection, as ROS could also acti- et al. 2014; Counter et al. 2014;Liet al. 2014; Soleimani vate the innate immune response through TLR signalling et al. 2014; Winiarska-Mieczan 2014; dos Santos et al. (Jin et al. 2017). Similar to ROS, RNS plays an important 2015; Al-Saleh et al. 2016; Dursun et al. 2016; Kunter et al. role in the innate immune response. Nitric oxide released - 2016; Song et al. 2016). Initially it was associated with the mainly by macrophages and neutrophils reacts with O2 free high levels of heavy metals in human and animal fluids were radicals generated from ROS yielding RNS which in defence due to environmental contamination and dietary habits, but mechanisms induce DNA damage and cell death that could now it is well known that a common distribution of these extend to the host uninfected cells (Blaser et al. 2016). elements are found in Earth’s crust (Rebelo and Caldas The influence of environmental factors on the host parasite 2016). Inorganic and organic compounds, heterogeneously interplay, exemplified by the contrasting functions of Tax and distributed in different geographic coordinates, that do not HBZ viral proteins, which modulate the virus behaviour in play a physiological role in cellular metabolism, are known the host infected cells, mainly decide the fate of viral infec- as xenobiotics. The natural introduction of stressors as tion and disease progression (Panfil et al. 2016; Al-Saleem chemical xenobiotics and derived compounds of different et al. 2017). The interplay among proteins encoded by microorganisms and plants (mycotoxins and phytochemi- HTLV-1 and host transcriptional products, generated as a cals) in the living organism, particularly the human being, consequence of infection and progression to disease, seems induces in the cell microenvironment, the production of not to be a fortuitous event, but a myriad of concerted actions reactive oxygen species (ROS) and reactive nitrogen species for the virion, as a biological entity, eager to replicate, to HTLV-1 escape 791 escape from a stressed cell before being sacrificed when the Agoni L, Lenz J and Guha C 2013 Variant splicing and influence of cell dies, metaphorically expressing. On the other hand, ionizing radiation on human endogenous retrovirus K (HERV-K) healthy cells keep up the provirus protected, being passed to transcripts in cancer cell lines. PLoS One 8 e76472 the progeny. Sometimes we would hypothesize that HTLV-1 Al-Saleem J, Kvaratskhelia M and Green PL 2017 Methods for would participate in human population control with other identifying and examining HTLV-1 HBZ post-translational organisms, in large cities, with overcrowding communities, modifications. Methods Mol. Biol. 1582 111–126 Al-Saleh I, Nester M, Abduljabbar M, Al-Rouqi R, Eltabache C, when it is observed that the quality of life is not improved, Al-Rajudi T and Elkhatib R 2016 Mercury (Hg) exposure and its and the genome exposition to harmful and different sources effects on Saudi breastfed infant’s neurodevelopment. Int. of physical, chemical or biological toxics takes place, com- J. Hyg. Environ. Health. 219 129–141 promising the virus genome and survival. 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Corresponding editor: SAUMITRA DAS